Conditions: Familial Chylomicronemia Syndrome Lipoprotein Lipase Deficiency Hyperlipoproteinemia Type 1
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
An open-label study of volanesorsen (ISIS 304801) administered subcutaneously to participants with FCS.

Detailed description:
This is a multi-center, open-label study for FCS participants rolling over from the ISIS 304801-CS6 (NCT02211209) index study, FCS participants rolling over from the ISIS 304801-CS16 (NCT02300233) index study and Treatment-naïve group. All participants were to receive volanesorsen 300 milligrams (mg) once per week for 52 weeks. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Participants had the option of continuing dosing for an additional 52 weeks (France: up to an additional 104 weeks for a total of 156 weeks) until an expanded access program was approved and available in their country. Participants who were not participating in an expanded access program were to enter a 13-week (France: 26-week) post-treatment evaluation period.

Arms:
arm 1: Treatment naïve group included combined group of ISIS 304801-CS7 (CS7-New) study participant and participant on placebo in index studies (ISIS 304801-CS6 \[NCT02211209\] and ISIS 304801-CS16 \[NCT02300233\]), were to receive 300 mg of volanesorsen as single SC once weekly for Weeks 1-52 of this study. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Following Week 52 visit, participants had option of participating in expanded access program or continuing treatment with 300 mg of volanesorsen as single SC once-weekly for up to additional 52 weeks (Weeks 53-104) and in France participants, up to additional 104 weeks for total of 156 weeks (Weeks 105 to Week 156) until expanded access program was approved and available in their country. Participants who were not participating in expanded access program were to enter 13-week post-treatment (PT) evaluation period and in France, participants not continuing treatment were to enter 26-week PT follow-up period. arm 2: Participants with FCS rolling over from the ISIS 304801-CS6 (NCT02211209) index study after receiving volanesorsen, were to receive 300 mg of volanesorsen as a single SC injection once weekly for Weeks 1-52 of this study. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Following the Week 52 visit, participants had the option of participating in an expanded access program or continuing treatment with 300 mg of volanesorsen as a single SC injection once-weekly for up to an additional 52 weeks (Weeks 53-104) and in France participants, up to an additional 104 weeks for total of 156 weeks of treatment (Weeks 105 to Week 156) of this study until an expanded access program was approved and available in their country. Participants who were not participating in an expanded access program were to enter a 13-week post-treatment evaluation period and in France, participants not continuing treatment were to enter a 26-week post-treatment follow-up period. arm 3: Participants with FCS rolling over from the ISIS 304801-CS16 (NCT02300233) index study after receiving volanesorsen, were to receive 300 mg of volanesorsen as a single SC injection once weekly for Weeks 1-52 of this study. Participants were allowed dose adjustment/dose reduction based on monitoring rules. Following the Week 52 visit, participants had the option of participating in an expanded access program or continuing treatment with 300 mg of volanesorsen as a single SC injection once-weekly for up to an additional 52 weeks (Weeks 53-104) and in France participants, up to an additional 104 weeks for total of 156 weeks of treatment (Weeks 105 to Week 156) of this study until an expanded access program was approved and available in their country. Participants who were not participating in an expanded access program were to enter a 13-week post-treatment evaluation period and in France, participants not continuing treatment were to enter a 26-week post-treatment follow-up period.

Interventions: intervention 1: Volanesorsen
Intervention descriptions: intervention 1: 300 mg volanesorsen administered via SC injection.

Protocol document:
Prot_000.pdf: 
Official Title:        
NCT Number: 
Document Dates: 
ISIS 304801-CS7 The APPROACH Open Label Study Volanesorsen (ISIS 
304801) An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients With Familial Chylomicronemia Syndrome 
(FCS)
 NCT02658175
Protocol Amendment 10 - France: 01 May 2019 
Protocol Amendment 9: 25 May 2018 
Amendment 8: 10 April 2017 
Amendment 7: 3 February 2017  Protocol 
Amendment 6: 16 September 2016  Protocol 
Protocol Amendment 5: 19 August 2016  Protocol 
Protocol Amendment 4: 6 June 2016 
Protocol Amendment 3: 9 May 2016 
Amendment 2: 22 April 2016  
Protocol Amendment 1: 2 February 2016  Protocol  
Original Protocol: 28 August 2015
 
 


Sponsor: 
Akcea Therapeutics 
22 Boston Wharf Road, 9th Floor 
Boston, MA  02210 
  Collaborator: 
  Ionis Pharmaceuticals, Inc. 
  2855 Gazelle Court 
  Carlsbad, CA  92010 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801)
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 10 - France – 01 May 2019 
EudraCT No:  2015-003755-21 


ISIS 304801-CS7 
Protocol - France 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment I 0 
01 May2019 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 10 - France - 01 May 2019 
Protocol History: 
Original Protocol: 
28 August 2015 
Protocol Amendment 1: 2 February 2016 
Protocol Amendment 2: 22 April 2016 
Protocol Amendment 3: 9 May 2016 
Protocol Amendment 4: 6 June 2016 
Protocol Amendment 5: 19 August 2016 
Protocol Amendment 6: 16 September 2016 
Protocol Amendment 7: 3 February 2017 
Protocol Amendment 8: 10 April 2017 
Protocol Amendment 9: 25 May 20 I 8 
Approved by: 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
Telephone: 
 
 MD 
Akcea Therapeutics, Inc. 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
3 
Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 10 - France 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
Telephone: 
 
Key Sponsor Contact: 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor  
Boston, MA 02210 
Phone: 
 
Email: 
 
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court  
Carlsbad, CA 92010  
Date: 
01 May 2019  
Confidentiality Statement 
This document contains confidential information of Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, 
Inc. that must not be disclosed to anyone other than the recipient study staff and members of the 
independent ethics committee, institutional review board, or authorized regulatory agencies.  This 
information cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, 
Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
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4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to Patients 
with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 10 - France 
Date:  
 
01 May 2019 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An Open-
Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS)”, Amendment 10 – France, dated 01 May 2019, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on Good 
Clinical Practice E6 (R2). 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
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5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT .................................................................................................................. 10 
PROTOCOL SYNOPSIS ......................................................................................................................... 22 
STUDY DESIGN AND TREATMENT SCHEMA ................................................................................ 28 
1. 
OBJECTIVES .............................................................................................................................. 32 
2. 
BACKGROUND AND RATIONALE ....................................................................................... 32 
2.1 
Overview of Disease.................................................................................................................. 32 
2.2 
Therapeutic Rationale ................................................................................................................ 33 
2.3 
Volanesorsen ............................................................................................................................. 34 
2.3.1 
Mechanism of Action ........................................................................................................ 34 
2.3.2 
Chemistry .......................................................................................................................... 35 
2.3.3 
Preclinical Experience ....................................................................................................... 35 
2.3.4 
Clinical Experience ........................................................................................................... 36 
2.4 
Rationale for Dose and Schedule of Administration ................................................................. 38 
3. 
EXPERIMENTAL PLAN ........................................................................................................... 38 
3.1 
Study Design ............................................................................................................................. 38 
3.2 
Number of Study Centers .......................................................................................................... 39 
3.3 
Number of Patients .................................................................................................................... 39 
3.4 
Overall Study Duration and Follow-up ..................................................................................... 39 
3.4.1 
Qualification ...................................................................................................................... 39 
3.4.2 
Treatment .......................................................................................................................... 39 
3.4.3 
Extended Treatment Period ............................................................................................... 39 
3.4.4 
Post-Treatment Follow-Up ................................................................................................ 39 
3.5 
End-of-Study ............................................................................................................................. 40 
3.6 
Data and Safety Monitoring Board ............................................................................................ 40 
4. 
PATIENT ENROLLMENT ........................................................................................................ 40 
4.1 
Qualification .............................................................................................................................. 40 
4.2 
Enrollment ................................................................................................................................. 40 
5. 
PATIENT ELIGIBILITY ........................................................................................................... 40 
5.1 
Inclusion Criteria ....................................................................................................................... 40 
5.2 
Exclusion Criteria ...................................................................................................................... 41 
6. 
STUDY PROCEDURES ............................................................................................................. 44 
6.1 
Study Schedule .......................................................................................................................... 44 
6.1.1 
Qualification ...................................................................................................................... 44 
6.1.2 
Treatment Period ............................................................................................................... 44 
6.1.3 
Extended Treatment Period ............................................................................................... 44 
6.1.4 
Pharmacokinetic (PK) Subgroup ....................................................................................... 45 


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6.1.5 
Post-Treatment Follow-up ................................................................................................. 45 
6.2 
Additional Study Assessments .................................................................................................. 45 
6.2.1 
Laboratory Assessments .................................................................................................... 45 
6.2.2 
Physical Exams and Vital Signs ........................................................................................ 46 
6.2.2.1 
Eruptive Xanthoma..................................................................................................... 46 
6.2.2.2 
Lipemia Retinalis ....................................................................................................... 46 
6.2.3 
Echocardiography .............................................................................................................. 46 
6.2.4 
ECG 
 ............................................................................................................................ 46 
6.2.5 
MRI 
 ............................................................................................................................ 47 
6.2.6 
Quality of Life Assessments .............................................................................................. 47 
6.2.7 
Disease Symptom Diary .................................................................................................... 47 
6.2.8 
Diet Monitoring ................................................................................................................. 47 
6.2.9 
Family History ................................................................................................................... 47 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) ............. 47 
6.3 
Restriction on the Lifestyle of Patients...................................................................................... 47 
6.3.1 
Contraception Requirements ............................................................................................. 47 
6.3.2 
Other Requirements ........................................................................................................... 48 
7. 
STUDY DRUG ............................................................................................................................. 49 
7.1 
Volanesorsen Description .......................................................................................................... 49 
7.2 
Packaging and Labeling ............................................................................................................ 49 
7.3 
Study Drug Accountability ........................................................................................................ 49 
8. 
TREATMENT OF PATIENTS .................................................................................................. 49 
8.1 
Volanesorsen Administration .................................................................................................... 49 
8.2 
Other Protocol-Required Drugs ................................................................................................. 50 
8.3 
Other Protocol-Required Treatment Procedures ....................................................................... 50 
8.4 
Treatment Precautions ............................................................................................................... 50 
8.5 
Safety Monitoring Rules ............................................................................................................ 50 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ................................................................... 51 
8.5.2 
Safety Monitoring for Platelet Count Results ................................................................... 51 
8.5.3 
Safety Monitoring for Minor Bleeding Events .................................................................. 53 
8.5.4 
Safety Monitoring for Constitutional Symptoms .............................................................. 53 
8.5.5 
Safety Monitoring for LDL-C Elevations ......................................................................... 53 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...................... 53 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia .............................................. 54 
8.5.8 
Safety Monitoring for Hyperglycemia .............................................................................. 55 
8.5.9 
Acute Pancreatitis .............................................................................................................. 55 
8.6 
Stopping Rules .......................................................................................................................... 56 
8.6.1 
Stopping Rules for Liver Chemistry Elevations ................................................................ 56 


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8.6.2 
Stopping Rules for Renal Function Test Results ............................................................... 56 
8.6.3 
Stopping Rules for Platelet Count Results ........................................................................ 56 
8.7 
Adjustment of Dose Frequency ................................................................................................. 59 
8.8 
Discontinuation of Study Treatment ......................................................................................... 59 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...................................... 60 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period ............. 60 
8.9 
Withdrawal of Patients from the Study ..................................................................................... 60 
8.10 
Concomitant Therapy and Procedures ....................................................................................... 61 
8.10.1 
Concomitant Therapy ........................................................................................................ 61 
8.10.2 
Concomitant Procedures .................................................................................................... 61 
8.11 
Treatment Compliance .............................................................................................................. 62 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................... 62 
9.1 
Sponsor Review of Safety Information ..................................................................................... 62 
9.2 
Regulatory Requirements .......................................................................................................... 62 
9.3 
Definitions ................................................................................................................................. 63 
9.3.1 
Adverse Event ................................................................................................................... 63 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ......................................................... 63 
9.3.3 
Serious Adverse Event (SAE) ........................................................................................... 63 
9.4 
Monitoring and Recording Adverse Events .............................................................................. 64 
9.4.1 
Serious Adverse Events ..................................................................................................... 64 
9.4.2 
Non-Serious Adverse Events ............................................................................................. 64 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ................................................ 64 
9.4.3.1 
Relationship to the Study Drug .................................................................................. 64 
9.4.3.2 
Severity....................................................................................................................... 65 
9.4.3.3 
Action Taken with Volanesorsen ............................................................................... 65 
9.4.3.4 
Treatment Given for Adverse Event........................................................................... 65 
9.4.3.5 
Outcome of the Adverse Event .................................................................................. 65 
9.4.4 
Adjudication Committees .................................................................................................. 66 
9.5 
Procedures for Handling Special Situations .............................................................................. 66 
9.5.1 
Abnormalities of Laboratory Tests .................................................................................... 66 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ....................... 66 
9.5.3 
Treatment Errors................................................................................................................ 67 
9.5.4 
Contraception and Pregnancy ............................................................................................ 67 
10. 
STATISTICAL CONSIDERATIONS ....................................................................................... 68 
10.1 
Study Endpoints ........................................................................................................................ 68 
10.1.1 
Efficacy Endpoints ............................................................................................................ 68 
10.1.2 
Safety Endpoints................................................................................................................ 68 
10.2 
Sample Size ............................................................................................................................... 68 


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10.3 
Populations ................................................................................................................................ 69 
10.4 
Definition of Baseline................................................................................................................ 69 
10.5 
Interim Analysis ........................................................................................................................ 69 
10.6 
Planned Methods of Analysis .................................................................................................... 69 
10.6.1 
Demographic and Baseline Characteristics ....................................................................... 70 
10.6.2 
Safety Analysis .................................................................................................................. 70 
10.6.3 
Efficacy Analysis .............................................................................................................. 70 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ............................................................... 71 
10.6.4.1 
Pharmacokinetic Analysis .......................................................................................... 71 
10.6.4.2 
Immunogenicity Analysis........................................................................................... 71 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS .......................................................... 72 
11.1 
Informed Consent ...................................................................................................................... 72 
11.2 
Ethical Conduct of the Study ..................................................................................................... 72 
11.3 
Independent Ethics Committee/Institutional Review Board ..................................................... 72 
11.4 
Patient Confidentiality ............................................................................................................... 73 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .............................................................. 73 
12.1 
Protocol Amendments ............................................................................................................... 73 
12.2 
Study Termination ..................................................................................................................... 73 
12.3 
Study Documentation and Storage ............................................................................................ 73 
12.4 
Study Monitoring ...................................................................................................................... 74 
12.5 
Language ................................................................................................................................... 74 
12.6 
Compensation for Injury ............................................................................................................ 75 
13. 
REFERENCES ............................................................................................................................. 76 
14. 
APPENDICES .............................................................................................................................. 79 
Appendix A 
Schedule of Procedures .............................................................................................. 79 
Appendix B 
List of Laboratory Analytes ....................................................................................... 90 
Appendix C 
Pharmacokinetic Sampling Schedule ......................................................................... 92 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities ................ 95 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics .................................................................... 49 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower 
Limit of Normal (×2) or < 100,000/mm3 (×1)* ................................................................ 52 
Table 3 
Actions in Patients with Low Platelet Count .................................................................... 58 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and the 
Expected Incidence ........................................................................................................... 62 
 


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TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .......................... 33 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ............................................... 35 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen........................... 37 
 


ISIS 304801-CS7 
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PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment Number:  
10 - France 
Amendment Date: 
01 May 2019 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol ISIS 
304801-CS7 Amendment 9 - France dated 25 May 2018:  
• 
To add an up to 52 weeks of additional treatment to the Extended Treatment Period, to clarify the 
option for patients to receive a volanesorsen dose reduction of 300 mg every two weeks, to clarify 
discontinuation of patients from the treatment period who are on a dose pause for ≥ 3 months, and 
to remove the references to landmark visits (if patient stops treatment then they enter the follow-
up period). 
Minor changes (not included in the list of changes below) have been made throughout the protocol to 
correct errors and/or to improve the overall clarity of the original protocol but these changes do not 
impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol, additions are indicated as 
underline and deletions are indicated as strikethrough: 
Protocol Section 
Description of Change 
Rationale 
Section 2.3.4 
Clinical 
Experience 
Volanesorsen has been evaluated in one Phase 1 study 
and two Phase 2 studies, all double blinded and 
placebo controlled.  The total exposures comprise 99 
patients and healthy volunteers administered 
volanesorsen from 50 to 400 mg subcutaneously up to 
3 months (compared to 37 administered placebo).The 
clinical experience with volanesorsen includes clinical 
trials in healthy subjects, patients with 
hypertriglyceridemia, FCS, or familial partial 
lipodystrophy. Overall, 431 patients and healthy 
volunteers have taken part in the clinical development 
program, of whom 325 have received at least 1 dose of 
volanesorsen. Ninety-five (95) patients with FCS have 
been enrolled in studies, all showing clinically 
meaningful reductions in plasma triglyceride. Patients 
with FCS continue on treatment in the open-label 
extension (OLE) and triglyceride reductions persist at 
similar levels as reported in earlier studies.  
In the completed Phase 1 and Phase 2 studies, 
volanesorsen was well-tolerated and demonstrated a 
favorable safety profile. There was no clinical or 
laboratory evidence of drug-drug interactions despite 
many patients in the Phase 2 clinical trials receiving 
Update language regarding 
clinical experience in Phase 1 and 
2 studies and incidence of AEs in 
completed Phase 3 studies and 
update to language regarding 
safety risks of Study Drug. 
 


ISIS 304801-CS7 
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11 
concomitant medications that are known to be 
associated with elevations in hepatic enzymes, such as 
fibrates and statins. There were no volanesorsen-
associated laboratory abnormalities suggestive of an 
effect on the renal (serum creatinine, proteinuria) or 
hepatic systems (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], bilirubin). There was 
a reduction (mean reduction < 30%) in platelets in 
volanesorsen vs. placebo with mean nadirs for all doses 
remaining above the lower limit of normal (LLN). The 
most frequently reported adverse events (AEs) were 
mild, non-progressive events at the injection site. In 
Phase 2, a single serious adverse event (SAE) of 
secondary serum sickness-like reaction was reported 
as related to Study Drug. 
… 
In the completed pooled Phase 3 studies (ISIS 304801-
CS6 (hereafter referred to as CS6) and ISIS 304801-
CS16 (hereafter referred to as CS16), the most 
common AEs associated with volanesorsen 
administration were tolerability at the injection site and 
platelet reductions. The majority of the injection site 
AEs were mild, none were severe, and the incidence 
appeared to decrease over time. No deaths have been 
associated with volanesorsen treatment to date. No 
cardiac toxicity was associated with volanesorsen 
treatment. There were no abnormal QTc findings and 
no study-drug related adjudicated major adverse 
cardiac events (MACE). There is no evident association 
between volanesorsen treatment and changes in renal 
or liver functions.In clinical studies conducted to date 
volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or 
laboratory evidence of drug-drug interactions. 
The safety profile of volanesorsen has been well-
described in this development program, which has 
identified 3 safety risks: thrombocytopenia (an identified 
risk), constitutional symptoms (flu-like reactions and 
influenza-like illness), and injection site reactions (a 
tolerability signal). Spontaneous, mild to severe 
thrombocytopenia has been described in the FCS 
patient population (Gaudet et al. 2017) but is increased 
by treatment with volanesorsen. Less frequent and less 
pronounced platelet declines were also observed with 
volanesorsen treatment in the hypertriglyceridemic 
(HTG) population of CS16. When fully complied with, 
frequent monitoring for this effect and appropriate dose 
adjustments have been successful both in preventing 
and promptly detecting the occurrence of severe 
platelet declines and often in retaining patients on 
treatment.In the completed studies there have been no 
volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, 
proteinuria) or hepatic systems (alanine 


ISIS 304801-CS7 
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aminotransferase [ALT], aspartate aminotransferase 
[AST], bilirubin).  In Phase 2 studies, there was a mild 
decrease of platelet count associated with volanesorsen 
administration that recovered in the post-treatment 
period and was not associated with platelet-related 
adverse events (AEs).  In the blinded ongoing clinical 
trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to 
less than 50,000/mm3 in the absence of major bleeding 
or clinically-relevant non-major bleeding and had Study 
Drug paused as per the monitoring and stopping rules 
for platelet counts (Section 8.6.3).  Platelet counts 
recovered following suspension of dosing. 
The most frequently observed AEs with volanesorsen 
were local reactions at the injection site.  Local 
cutaneous reactions at the injection site defined as 
those events presenting as either pain, tenderness, 
erythema, pruritus or swelling occurring on the day of 
injection and persisting for at least 2 days were 
infrequent (~15% of injections), were almost always 
mild, resolved spontaneously, were non-progressive, 
and were not associated with systemic sequelae. 
Section 2.4 
Rationale for 
Dose and 
Schedule of 
Administration 
The dose and schedule selected for this study is 300 
mg per week for 52 weeks, with the option of continuing 
dosingtreatment for up to an additional 52104 weeks.  
The dose of 300 mg per week and dose reduction of 
300 mg every 2 weeks (delivered as a single 300 mg 
dose) are is supported by both the cumulative 
nonclinical data available to date and the Phase 2 
clinical data. 
… 
No nonNon clinical findings were not considered to be 
related to the pharmacologic inhibition of apoC-III. 
… 
In addition to the nonclinical and clinical experience of 
volanesorsen, the dose and schedule of administration 
is supported by the preclinical and clinical safety 
experience of several other 2′ MOE-modified ASOs that 
have been safely administered intravenously and 
subcutaneously in multiple clinical studies at doses up 
to 10001200 mg and for treatment durations that 
exceed 24 months (Santos et al. 2015). 
Language added to clarify dose 
reductions as 300 mg every 2 
weeks according to patient’s 
tolerability on the 300 mg weekly 
dose, given similar extents of 
triglyceride lowering anticipated 
based on population 
pharmacokinetic/ 
pharmacodynamic model-based 
simulations. 
 
 
 
Updated to reflect data presented 
in source listed. 
 
Synopsis: Study 
Design, Study 
Visit Schedule 
and Procedures 
 
 
 
Synopsis 
All patients will receive volanesorsen 300 mg once per 
week for 52 weeks.  Dietary counseling will be 
reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients 
will have the option to continue dosing treatment for up 
to an additional 52104 weeks for a total of up to 156 
weeks of dosing treatment.  Patients not continuing 
Edited length of Extended 
Treatment Period to allow patients 
in France to continue to receive 
study drug until commercialization 
of product.  


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Section 3.1 
Study Design 
 
 
 
 
 
Section 6.1.3 
Extended 
Treatment Period 
dosing treatment will enter a 26-week post-treatment 
follow-up period. 
Section 3.1 
Following the Week 52 visit, patients will have the 
option to continue dosingtreatment for up to an 
additional 52104 weeks for a total of 104up to 156 
weeks of dosing treatment. Patients not to continuing 
dosing treatment will enter a 26-week post-treatment 
follow-up period.   
Section6.1.3 
After completion of the Week 52 visit assessments, 
patients will have the option of continuing dosing for up 
to an additional 52 weeks treatment for up to an 
additional 104 weeks.  For patients that have entered 
the Extended Treatment Periods, study participation will 
be up to an additional 104 weeks or until 
commercialization of product, whichever is sooner. 
During the extended treatment period, patients will have 
assessments and procedures done during Weeks 54-
104156 as per the Schedule of Procedures in 
Appendix A 
Section 3.4.3 
Extended 
Treatment Period 
 
Following the Week 52 visit, patients will have the 
option to continue dosing treatment for up to an 
additional 52104 weeks. Patients not to continuing 
dosing treatment will enter a 26-week post-treatment 
follow-up period. For patients that have entered the 
Extended Treatment Periods, study participation will be 
up to an additional 104 weeks or until commercialization 
of product, whichever is sooner 
Edited length of Extended 
Treatment Period to allow patients 
in France to continue to receive 
study drug until commercialization 
of product. 
Section 3.4.4 
Post-Treatment 
Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
Section 3.4.4 
The post-treatment follow-up period is at least 26 weeks 
and consists of at least 9 Study Center visits.  For 
patients not continuing into the 52-week extended 
treatment period, the post-treatment follow-up period 
visits will be conducted on Weeks 53, 54, 55, 56, 57, 
58, 65, 71, and 78 (Weeks 53, 54, 55, 56, 57, 58, and 
71 may be conducted by a home healthcare nurse). 
For patients who have entered the first 52-week 
extended treatment period, but will not continue into the 
second 52-weeks of the extended treatment period, the 
post-treatment follow-up period visits will be conducted 
on Weeks 105, 106, 107, 108, 109, 110, 117, 123 and 
130 (Weeks 105, 106, 107, 108, 109, 110 and 123 may 
be conducted by a home healthcare nurse). 
For patients who have entered the second 52-week 
extended treatment period, the post-treatment follow-up 
period visits will be on Weeks 157, 158, 159, 160, 161, 
162, 169, 175 and 182 (Weeks 157, 158, 159, 160, 161, 
162 and 175 may be conducted by a home healthcare 
nurse). 
Section 6.1.5 
Added details of follow-up period 
for the first and second Extended 
Treatment Periods. 


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Section 6.1.5 
Post-Treatment 
Follow-Up 
After completion of the Week 52 visit assessments, 
patients will have the option of continuing dosing 
treatment for up to an additional 52104 weeks as 
described in Section 6.1.3.  Patients not continuing 
dosing treatment will enter the 26-week post treatment 
follow-up.  The 26For patients not continuing into the 
52-week extended treatment period, the 26-week post-
treatment follow-up period consists of at least 9  Study 
Center visits on Weeks 53, 54, 55, 56, 57, 58, 65, 71, 
and 78 (Weeks 53, 54, 55, 56, 57, 58, and 71 may be 
conducted by a home healthcare nurse). An additional 
26 
For patients who enter the first 52-week post-treatment 
follow-up occurs afterextended treatment period, but will 
not continue into the second 52-weeks of the extended 
treatment period with at least 9 Study Center, the post-
treatment follow-up period visits will be conducted on 
Weeks 105, 106, 107, 108, 109, 110, 117, 118,123 and 
125130 (Weeks 105, 106, 107, 108, 109, 110 and 
118123 may be conducted by a home healthcare 
nurse).  
For patients who enter the second 52-week extended 
treatment period, the post-treatment follow-up period 
visits will be on Weeks 157, 158, 159, 160, 161, 162, 
169, 175 and 182 (Weeks 157, 158, 159, 160, 161, 162 
and 175 may be conducted by a home healthcare 
nurse). 
Section 5.2 
Exclusion Criteria  
Synopsis, Study 
Population 
14. 
Use of any of the following: 
… 
c. 
Systemic corticosteroids or anabolic 
steroids within 6 weeks prior to 
Qualification unless approved by the 
Sponsor Medical Monitor 
… 
16. 
Known hypersensitivity to any of the excipients 
of the Study Drug (ISIS 304801 or placebo) 
Exceptions to inclusion or 
exclusion criteria will not be 
granted. 
Section 6.1.3 
Extended 
Treatment Period 
Blood sampling will be conducted weekly at Weeks 53, 
54, 55, 56, 57, 58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 
70, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 
86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 
101, 102, and 103 may be conducted by a home 
healthcare nurse 
Modified to indicate that blood 
sampling will occur weekly for 
increased clarity and to include an 
up to 104 additional weeks of 
extended treatment. 
Section 6.2.1 
Laboratory 
Assessments 
Section 8.5.4 
Safety Monitoring 
for Constitutional 
Symptoms 
Should a patient experience constitutional or flu-like 
symptoms after Study Drug administration, investigators 
may consider additional laboratory assessments.  For 
example, plasma and serum samples may be drawn for 
complement (Total C3, C4, C5a and Bb), high-
sensitivity C-reactive protein (hsCRP) and for cytokine 
analysis. 
To add additional laboratory 
assessments permitted for safety 
purposes. 


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Section 6.2.4 
ECG 
Patients in the Extended Treatment Periods will have 
ECGs performed in triplicate at Weeks 76 and, 104. and 
130. Triplicate ECGs will be performed at Weeks 13 
and 26 of each post-treatment follow-up period. 
To detail additional ECG 
assessments in the post-
treatment follow-up period. 
Section 6.2.6 
Quality of Life 
Assessments 
Should the patient enter the extended treatment 
periods, Aadditional Quality of Life Questionnaires will 
be collected at Weeks 1713 and 130 26 of each should 
the patient enter the extended treatment period post-
treatment follow- up period. 
To detail additional QoL 
assessments in the post-
treatment follow-up period. 
Section 8.1 
Volanesorsen 
Administration 
For each individual patient, volanesorsen will be 
administered subcutaneously as a single 1.5 mL 300 
mg injection once weekly for Weeks 1-52.  Patients 
entering this ISIS 304801-CS7 study on a reduced dose 
or dose frequency of Study Drug (volanesorsen), for 
safety or tolerability reasons in their index study (ISIS 
304801-CS6 or ISIS 304801-CS16), will continue to 
receive study drug as a single 300 mg/1.5 mL injection 
once-weekly for Weeks 53-156104 receive a reduced 
dose or dose frequency of volanesorsen for continued 
safety or tolerability as outlined in Sections 8.5 and 8.6.  
Patients on dose reduction will receive 300 mg/1.5 mL 
injections every 2 weeks entering this CS7 study having 
dose or dose frequency reduced in the CS16 index 
study after 13 weeks of treatment, as outlined in CS16 
Amendment 4 Section 8.7, can receive the 300 mg 
once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, unless on a 
dose reduction of 300 mg every 2 weeks, with weeks 
always defined relative to Study Day 1. 
Added language clarifying details 
of dose reduction option as 
300 mg every 2 weeks. 
Section 8.5.2 
Safety Monitoring 
for Platelet Count 
Results 
Monitor every 1 week unless otherwise specified. In 
addition, platelet function may be evaluated at any time 
during the study by aggregometry, using an approved 
point-of-care diagnostic device, in some patients.  This 
additional functional testing may be performed at 
selected study centers. 
… 
Due to the 1 to 32-year study duration it is anticipated 
that patients may undertake travel including vacations, 
which may impede weekly platelet monitoring.  In some 
situations, it may be possible to arrange for local 
laboratory testing or use of the home healthcare service 
at their temporary location.  The intent is to maintain 
weekly platelet monitoring and dosing treatment where 
possible, as well as Investigator site contact with the 
study patients.  However, if the above options are not 
possible, a temporary interruption of study treatment will 
be planned with a platelet count drawn within 3-5 days 
prior to departure and with a prompt blood draw upon 
the patient’s return which must be reported and 
reviewed by the Investigator prior to the patient 
resuming dosing treatment. 
Additional point-of-care platelet 
function testing may be conducted 
on patients at participating study 
centers.   
 
 
 
Included an additional blood draw 
to assess platelet count prior to 
any travel that would result in 
missing a weekly monitoring visit.   


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Patients on dose pause should be monitored as per the 
platelet monitoring rules outlined in Section 8.8.1 until 
Study Drug administration is resumed. 
Section 8.6.3 
Stopping Rules 
for Platelet Count 
Results 
Table 3 Actions in Patients with Low Platelet Count 
Platelet 
Count on 
Rx 
Drug Dose 
Monitoring 
Study Drug 
administration 
is contingent 
on the 
availability of 
the 
immediately 
preceding test 
result.  An 
interpretable 
platelet value 
must be 
available within 
7 days prior to 
dosing 
treatment.  
Only the study 
doctor or 
qualified 
designee can 
authorize 
continued 
Study Drug 
administration 
based on an 
acceptable 
platelet value.  
Patients 
should not 
administer a 
dose until they 
have been 
contacted by 
their study 
doctor or 
designee and 
told that it is 
acceptable to 
dose.  
Authorization 
to dose must 
be 
documented in 
the patient’s 
medical 
records. 
Monitor every 1 
week unless 
otherwise specified 
In addition, platelet 
function may be 
evaluated during 
the study by 
aggregometry, 
using an approved 
point- of-care 
diagnostic device, 
in some patients.  
This additional 
functional testing 
may be performed 
at selected study 
centers. 
Patients on dose 
pause should be 
monitored as per 
the platelet 
monitoring rules 
outlined in Section 
8.8.1 until Study 
Drug 
administration is 
resumed. 
Obtain additional 
lab tests (Table 2) 
if 2 occurrences 
(consecutive or 
non-consecutive) 
of platelet count  
140K - 
> 100K/mm3 or 1 
occurrence of 
platelet count ≤ 
100K/mm3.  Labs 
only need to be 
performed once.  
Labs may be 
collected over 
multiple visits, if 
blood requirements 
are a concern, as 
To provide clarification to the 
platelet safety monitoring rules, 
including dose reduction options. 


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per Investigator 
discretion. 
> 100K/mm3 
Once Wweekly 
300 mg Study 
Drug 
administration 
 
100K/mm3 - 
> 75K/mm3 
Permanently 
reduce dose 
frequency to 
300 mg every 
2 weeks.  
 
75K/mm3 
- > 50K/mm3 
If occurs while 
on dose of 300 
mg every 2 
weeks, then 
permanently 
discontinue 
Study Drug, 
otherwise dose 
pause. If dose 
pause is 
≥ 3 months 
then patient 
must 
discontinue 
treatment and 
enter the follow 
up period. 
When platelet 
count returns 
to > 100K/mm3 
restart dosing 
treatment at 
dose 
frequency of 
300 mg every 
2 weeks only if 
approved by in 
consultation 
with the 
Sponsor 
Medical 
Monitor 
Monitor every 2-3 
days until 
2 successive 
values are > 
75K/mm3 then 
monitor every 1 
week 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/ 
anticoagulant 
medication 
≤ 50K/mm3 
or a rate of 
decline ≥ 
50% 
between two 
consecutive 
assessment
s, 
irrespective 
of the 
platelet level 
Permanently 
discontinue 
Study Drug 
and the patient 
will enter the 
follow up 
period. 
• Monitor daily 
until 2 
successive 
values show 
improvement 
then monitor 
every  
2-3 days until 
2 successive 
values are 
> 75K/mm3 then 


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monitor every 
1 week 
• Patient should be 
evaluated by a 
hematologist to 
provide 
diagnostic and 
therapeutic 
management 
• Steroids 
recommended*.  
It is strongly 
recommended 
that, unless the 
patient has a 
medical 
contraindication 
to receiving 
glucocorticoids, 
the patient 
receives 
glucocorticoid 
therapy to 
reverse the 
platelet decline.   
• Monitor 
triglyceride levels 
weekly and 
continue AE 
monitoring during 
steroid therapy 
• Discontinue 
antiplatelet 
agents/ NSAIDS/ 
anticoagulant 
medication while 
platelet count is 
< 50K/mm3 if 
possible 
Section 8.7 
Adjustment of 
Dose Frequency 
Other dose adjustments, including dose interruptions, 
and/or decreasing the dose or dose frequency to 
300 mg every 2 weeks will be allowed for safety and 
tolerability.  Any proposed adjustment to treatment 
schedule must be discussed with, and approved by, the 
Study Medical Monitor prior to initiation.  Up to 2 
adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after 
consultation with, and the Study Medical Monitor is 
informed.  If a patient is dose paused for ≥ 3 months, he 
or she is considered to have discontinued treatment 
and should enter the 26-week post-treatment follow-up 
period. 
Clarification of dose reduction 
option to reduced dose frequency 
to allow for safety and tolerability 
 
Discontinuation of patients from 
the study who have been on dose 
pause and off study drug for >3 
months. 
 


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Section 8.8 
Discontinuation of 
Study Treatment 
A patient must permanently discontinue study treatment 
for any of the following: 
… 
•The patient is dose-paused for ≥ 3 months.
Added new treatment 
discontinuation criterion 
consistent with other protocol 
changes. 
Section 8.8.1 
Follow-up Visits 
for Early 
Termination from 
Treatment Period 
Any patient who discontinues early from the Treatment 
Period should be followed as per the platelet monitoring 
rules shown in Table 3 in Section 8.6.3 for the first 6 
weeks after discontinuing Study Drug.  Following this 
period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by 
the Sponsor Medical Monitor and > 100,000/mm3), the 
next platelet count should be taken within at least 6 
weeks so that patients are monitored for at least 12 
weeks after discontinuing Study Drug.  Patients should 
also be strongly encouraged to attend applicable 
landmark visits at Weeks 12, 13, 25, 26, and 50, 52 
(calculated based on the time elapsed since Day 1) to 
collect fasting lipid panels and conduct safety 
assessments in accordance with the Schedule of 
Procedures in Appendix A.  Any patient who 
discontinues treatment after Week 44 should also be 
strongly encouraged to attend a final follow-up visit 
(Week 78 visit assessments) approximately 26 weeks 
after their last dose of Study Drug. in addition to the 
applicable landmark visits. 
A patient who discontinues early from treatment with 
stable platelet counts above the LLN at the time of 
treatment discontinuation will have platelet counts 
drawn every 2 weeks after discontinuing Study Drug for 
the first 6 weeks after the last dose of Study Drug.  A 
subsequent platelet count should then be taken after an 
additional 6 weeks so that patients are monitored for at 
least 12 weeks after discontinuing Study Drug. 
Removal of language around 
landmark visits as patients who 
stop treatment now enter a post-
treatment follow-up period 
Provides guidance for platelet 
monitoring in the post-treatment 
follow-up period. 
Section 8.9 
Withdrawal of 
Patient from the 
Study 
Other reasons for withdrawal of patients from the study 
might include: 
• At the discretion of the Investigator for medical
reasons
• At the discretion of the Investigator or Sponsor for
noncompliance
• Significant protocol deviation
• Commercialization of product
Added commercialization of 
product as an additional reason 
for withdrawal from study. 
Section 8.10.2 
Concomitant 
Procedures 
Section 8.10.2 
A concomitant procedure is any therapeutic intervention 
(e.g., surgery/biopsy, physical therapy) or diagnostic 
assessment (e.g., blood gas measurement, bacterial 
cultures) performed between signing of informed 
consent and Week 78 (or Week 130 or 182 if the patient 
enters the first or second extended treatment period, 
respectively) visit. 
Updated to include follow-up 
period for the first and second 
Extended Treatment Periods. 


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Section 9.4.1  
Serious Adverse 
Events 
 
 
 
Section 9.4.2 
Non-Serious 
Adverse Events 
Section 9.4.1 
The collection of SAEs will begin after the patient signs 
the informed consent form and stop at the end of the 
patient’s follow-up period which is defined as the 
Week 78 (or Week 130 or 182 if the patient enters the 
first or second extended treatment period, respectively) 
visit. 
 
Section 9.4.2 
The recording of non-serious AEs will begin after the 
patient signs the informed consent form and will stop at 
the end of the patient’s follow-up period, which is 
defined as the Week 78 (or Week 130 or 182 if the 
patient enters the first or second extended treatment 
period, respectively) visit. 
Section 13 
REFERENCES 
Gaudet D, Baass A, Tremblay K, et al. Natural History 
(up to 15 years) of Platelet Count in 84 Patients with 
Familial Hyperchylomicronemia Due to Lipoprotein 
Lipase Deficiency. Journal of Clinical Lipidology 2017; 
11(3): 797-798. 
Addition of reference 
Section 14. 
APPENDICES 
Appendix A Schedule of Procedures 
The following footnotes have been added to the tables 
for both the qualification through treatment period and 
the post-treatment follow-up period. 
g 
Genetic testing can be conducted for study 
Qualification (Group 2 ISIS 304801-CS16 roll over 
patients); genetic testing will only be conducted if 
allowed in the geographic region and only after the 
patient has given specific written informed consent 
for genetic testing. A blood sample for potential 
gene sequencing may be collected at timepoints 
other than Screening or Qualification Visits. 
 
The table for the first 52-week extended treatment 
period and post-treatment follow-up period have been 
defined and additional tables added for the second 
52-weekextended treatment period and post-treatment 
follow-up period.   
 
Also added platelet function analysis to the first 
extended treatment period.  With Footnote g May be 
done 
Clarification that blood sampling 
for gene sequencing may occur 
during the study. 
 
 
 
 
 
 
 
 
 
Added an additional year of 
extended treatment  
 
 
 
Indication that platelet function 
may be assessed. 
Section  14. 
APPENDICES 
Appendix B List of Laboratory Analytes 
Platelet Function 
Platelet aggregation3 
Platelet function5 
Footnote 5: May be done using a point-of-care device 
on site. 
Addition of laboratory analyte to 
measure platelet function. 


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Section  14. 
APPENDICES 
Appendix C Pharmacokinetic Sampling Schedule 
 
Expanded PK Sampling Schedule to include timepoint 
for the First and Second 52-Week Extended Treatment 
Periods. 
Addition of PK sampling 
timepoints for additional year of 
extended treatment. 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of treatment and extended treatment with 
volanesorsen in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  Dietary 
counseling will be reinforced at intervals throughout the treatment and follow-up 
period.  Following the Week 52 visit, patients will have the option to continue 
treatment for up to an additional 104 weeks for a total of up to 156 weeks of 
treatment.  Patients not continuing treatment will enter a 26-week post-treatment 
follow-up period.  
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed and 
dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-
CS16 (index studies) with an acceptable safety profile, per Sponsor and 
Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the 
following criteria in order to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of lactescent 
serum (a creamy top layer after ultracentrifugation of a fasting blood 
sample) or documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of the 
following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-causing 
genes (such as lipoprotein lipase [LPL], apoC-II, GPIHBP1, or lipase 
maturation factor [LMF1]) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical 
history.  Note:  testing of LPL activity should not be performed to 
confirm eligibility for the study 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-
CS16 index study 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
4. 
Able and willing to participate in a 78-week study5. 
Satisfy 1 of the 
following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of spontaneous 
amenorrhea in females > 55 years of age or, in females ≤ 55 years, 12 
months of spontaneous amenorrhea without an alternative medical cause 
and follicle stimulating hormone (FSH) levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in sexual 
relations of child-bearing potential, patient is using an acceptable 
contraceptive method (refer to Section 6.3.1) from time of signing the 
informed consent form until 13 weeks after the last dose of Study Drug 
administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual relations 
with a female of child-bearing potential, patient is utilizing an acceptable 
contraceptive method (refer to Section 6.3.1) from the time of signing the 
informed consent form until 13 weeks after the last dose of Study Drug 
administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line 
with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial and withdrawal are not acceptable 
methods of contraception 
Exclusion Criteria: 
1. Diabetes mellitus with any of the following: 
a. 
Newly diagnosed within 12 weeks of Qualification 
b. HbA1c ≥ 9.0% at Qualification 
c. 
Recent change in anti-diabetic pharmacotherapy (change in dosage or 
addition of new medication within 12 weeks of Qualification [with the 
exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the treatment 
period of the Study (with the exception of ± 10 units of insulin) 
e. 
Current use of glucagon-like peptide-1 (GLP-1) agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to Qualification 
4. History within 6 months of Qualification of acute or unstable cardiac ischemia 
(myocardial infarction, acute coronary syndrome, new onset angina), stroke, 
transient ischemic attack or unstable congestive cardiac failure requiring a 
change in medication or major surgery within 3 months of Qualification 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
5. Any of the following laboratory values at Qualification 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which case 
total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein 
on urine dipstick.  In the event of a positive test eligibility may be 
confirmed by a quantitative total urine protein measurement of 
< 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace positive) 
for blood on urine dipstick.  In the event of a positive test 
eligibility may be confirmed with urine microscopy showing ≤ 5 
red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the formula 
of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault for 
estimation of glomerular filtration rate (GFR) in patients with low 
body weight after discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Qualification 
d. 
LDL-C > 130 mg/dL at Qualification 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding 
diathesis or coagulopathy or clinically-significant abnormality in coagulation 
parameters at Qualification 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will 
not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the 
skin or carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1 
month of Qualification, or 5 half-lives of investigational agent, whichever is 
longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and over-the-counter [OTC]), or 
fibrates unless on a stable dose for at least 3 months prior to Qualification 
and dose and regimen expected to remain constant during the treatment 
period.  Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
Qualification 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
Qualification  
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on 
a stable dose for at least 3 months prior to Qualification and dose and 
regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks 
prior to Qualification and dose and regimen expected to remain constant 
during the treatment period 
f. Glybera gene therapy within 2 years prior to Qualification 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) 
unless on a stable dose for at least 4 weeks prior to Qualification and regular 
clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 
months prior to Qualification and dose and regimen expected to remain 
constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to Qualification or planned during the 
study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to Qualification 
(Occasional or intermittent use of over-the-counter medications will be 
allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of > 499 mL 
within 60 days of Qualification 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801) 
17. Have any other conditions, including new or worsening of existing condition, 
which, in the opinion of the Investigator or the Sponsor would make the patient 
unsuitable for inclusion, or could interfere with the patient participating in or 
completing the study 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose frequency 
will be allowed for safety or tolerability after consultation with the Sponsor Medical 
Monitor. 


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PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and ISIS 304801-CS16) 
based on the pharmacodynamic and safety analysis of the Phase 2 studies 
(Section 2.4) which included a subset of patients with FCS.  The same dose of 
300 mg once weekly will be used in this open-label study of FCS patients.  
Study Visit Schedule and Procedures The study for an individual patient will generally consist of the following periods: 
• 
A qualification period of up to 2 weeks (unless approved by the Sponsor).  
Please refer to Section 4.1 and Appendix A 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
Option to participate in an extended treatment period (up to an 
additional 104 weeks) 
o 
A 26-week post-treatment follow-up period  
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid 
data through the last patient’s Week 13 visit of the open-label study or until results 
from the database locks for the ISIS 304801-CS6 and ISIS 304801-CS16 index 
studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), adverse events (AE), concomitant 
medication/procedure information, lipid panel, blood viscosity, volanesorsen plasma 
concentrations, immunogenicity (IM) testing, platelet aggregation, liver/spleen 
magnetic resonance imaging (MRI), electrocardiograms (ECGs), echocardiograms 
and quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will be 
completed for the week prior to each quarterly visit by each patient.  Following the 
Week 52 visit, patients will have the option to continue treatment for up to an 
additional 104 weeks. Patients not to continuing treatment will enter a 26-week post-
treatment follow-up period. 
Safety and Tolerability Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by determining the 
incidence and severity of adverse and serious adverse events (including 
independently adjudicated events of acute pancreatitis and MACE), withdrawals due 
to adverse events, and changes in laboratory and other safety parameters. 
 
 
 


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PROTOCOL SYNOPSIS Continued 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis and 
MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
ECGs 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during the 
treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III (apoC-
III) 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of volanesorsen 
as follows: trough levels (pre-dose) throughout treatment and post-treatment levels 
during the post-treatment follow-up period.  In a subset of patients, more frequent 
assessment of plasma concentrations of volanesorsen will be performed to determine 
volanesorsen pharmacokinetic parameters.  Plasma sample collection time points are 
detailed in Appendix A and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Akcea Therapeutics, Inc. 
Collaborator 
Ionis Pharmaceuticals, Inc. 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety 
assessments.  PK and PD/efficacy 
assessments at specified time points 
FIRST EXTENDED TREATMENT PERIOD 
Weeks 53 to 104 
SECOND EXTENDED TREATMENT 
PERIOD 
Weeks 105 to Week 156 
Patients will have the option to continue 
treatment for up to an additional 
104 weeks. 
POST-TREATMENT FOLLOW-UP 
Weeks 53 to 78* 
(Treatment Period Post Treatment Follow-
Up) 
 
And Weeks 105 to 130 
(FIRST Extended Treatment Period Post 
Treatment Follow-Up) 
 
And Weeks 157 to 182 
(SECOND Extended Treatment Period 
Post Treatment Follow-Up) 
 
Safety, efficacy, PK and PD assessments 
* If needed, the post-treatment follow-up 
period will be extended (with patients 
monitored every 6 weeks) until apoC-III 
levels return to baseline values 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
FSH 
follicle stimulating hormone 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 


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Abbreviation/Acronym 
Definition 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LLN 
Lower Limit of Normal 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SMPG 
self-monitored plasma glucose 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 


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Abbreviation/Acronym 
Definition 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 


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1.
OBJECTIVES
The objective of the study is to evaluate the safety and efficacy of treatment and extended treatment with 
volanesorsen in patients with familial chylomicronemia syndrome. 
2.
BACKGROUND AND RATIONALE
2.1 
Overview of Disease
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare autosomal 
recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above normal 
(1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 15-20% of daily 
calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in infancy or childhood with 
frequent and severe abdominal pain, repetitive colicky pain, repeated episodes of potentially fatal acute 
pancreatitis, and failure to thrive (Brunzell 1999-2011; Tremblay et al. 2011).  Physical examination 
frequently reveals eruptive xanthomas, lipemia retinalis and hepatosplenomegaly, and plasma from 
patients appears lactescent, interfering with determination of other laboratory parameters (Tremblay et 
al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of chylomicronemia.  
Clinical diagnosis would include evidence of clinical features of chylomicronemia syndrome and 
secondary causes such as uncontrolled type 1 or type 2 diabetes mellitus (T2DM), hypothyroidism, poor 
diet, alcohol use, nephrotic syndrome or use of associated medications should be ruled out.  The diagnosis 
of FCS may be made more specifically by genotyping or confirmation of very low or absent lipoprotein 
lipase (LPL) enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described above, 
being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent episodes of 
acute pancreatitis, these patients may also develop chronic pancreatitis and signs of exocrine or endocrine 
pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  While the pathophysiology 
underlying chylomicron-related pancreatitis has not been completely elucidated, 1 hypothesis is that large 
chylomicrons lodged in pancreatic capillaries are exposed to pancreatic lipase, with the subsequent 
release of free fatty acids through the hydrolysis of chylomicron-associated TGs.  High concentrations of 
free fatty acids are thought to damage pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; 
Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, skeletal 
muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL is regulated by a 
number of key genes, and loss-of-function mutations in one of these genes, or the LPL gene itself, results 
in FCS (Surendran et al. 2012).  In addition to loss of function mutations, null mutations, and nonsense 
mutations in the LPL gene, other genes currently identified in FCS patients, and known to directly 
influence LPL activity include: apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); 
apolipoprotein A-V (APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation factor 1 
(LMF1), a transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1), a 


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capillary endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major regulator 
of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels (Chan et al. 2008).  It is 
a component of triglyceride-rich lipoproteins (TRLs) and a potent inhibitor of LPL (Lemieux et al. 2003).  
At higher concentrations apoC-III also inhibits hepatic lipase activity (Kinnunen and Ehnolm 1976), an 
enzyme which plays an important role in the conversion of dense very-low-density lipoprotein (VLDL) to 
intermediate density lipoprotein (IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of 
HDL (Brown et al. 2010).  In addition, increased apoC-III content adversely affects apolipoprotein E 
(apoE)-mediated hepatic uptake of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III 
levels are associated with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the development of 
hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 
Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in inhibiting LPL, 


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apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by hepatic lipoprotein receptors 
by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or nonsense 
mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; Pollin et al. 2008; 
Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was identified in the heritability 
and phenotype intervention (HAPI) heart study in Old Order Amish that results in lower plasma apoC-III 
and TG levels and lower low-density lipoprotein-cholesterol (LDL-C), increased HDL-C and reduced 
atherosclerosis (Pollin et al. 2008).  In another study involving a group of 214 Ashkenazi Jews of 
advanced age (had passed or nearly reached 100 years of age), genotype analysis revealed a 
polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear pattern of age-dependent 
frequency that was associated with significantly lower levels of apoC-III protein, a favorable lipoprotein 
profile and increased longevity (Atzmon et al. 2006).  In contrast to the Amish and Ashkenazi apoC-III 
polymorphisms associated with lower plasma TG, apoC-III polymorphisms associated with higher plasma 
TG have also been recently described (Petersen et al. 2010).  In a cohort of lean (mean body mass index 
[BMI] = 24.7 ± 3.6 kg/m2) Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) 
were noted to have significantly higher plasma apoC-III and TG levels, and decreased ability to clear 
postprandial plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high circulating 
triglyceride and chylomicron levels that are accompanied by increasing risk for acute pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients who have no 
detectable LPL activity (See Section 2.3.4), and the mechanistic data available to date on apoC-III 
function, potential mechanisms that explain how apoC-III inhibition results in triglyceride reduction in 
FCS patients include:  (1) enhancing the very small residual amounts of LPL activity that these patients 
may have, below the limit of detection of the assay in many cases (2) potentially enhanced activity of 
other lipases also involved in the metabolism and breakdown of TGs, such as hepatic lipase or endothelial 
lipase (Kinnunen and Ehnolm 1976), and (3) apoC-III interaction with Apolipoprotein E (apoE), an 
important factor in liver reuptake of lipid particles by blocking apoE-mediated uptake of lipid particles in 
the liver (Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all of these 
mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential to 
manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human apoC-III.  It 
is complementary to a region within the 3ʹ untranslated region of the apoC-III messenger ribonucleic acid 
(mRNA) and binds to the mRNA by Watson and Crick base pairing.  The hybridization (binding) of 
volanesorsen to the cognate mRNA, results in the RNase H1-mediated degradation of the apoC-III 
mRNA, thus preventing production of the apoC-III protein.  Maximal antisense-mediated reduction of 
target mRNA levels is typically greater than 90% of control levels in sensitive tissues (Crooke and 
Bennett 1996; Zhang et al. 2010).  Furthermore, reduction in target mRNA levels using this approach 
correlates directly with a subsequent reduction in target protein levels. 


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2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are connected 
sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen (Figure 2) is 
complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the apoC-III mRNA 
transcript at base position 489-508.  Structurally, the oligonucleotide has 3 regions.  Two (2) of them, the 
5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are composed of 2ʹ-O-(2-methoxyethyl) 
(MOE)-modified ribonucleotides.  These MOE-modified nucleotides confer (1) increased affinity to the 
target mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of 
the high dose toxicities thereby resulting in an improved safety profile compared to first generation 
antisense drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 10 oligodeoxynucleotides.  
This chimeric design is called a MOE-Gapmer, and volanesorsen employs this chimeric structure to 
enable use of the RNase H1-mechanism for antisense activity.  This is because while the 2ʹ-MOE 
modification confers increased stability and affinity, it does not support RNase H1 catalysis of RNA 
hybridized to 2ʹ-MOE-modified nucleotides (McKay et al. 1999).  This is caused by conformational 
changes induced in the heteroduplex by 2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 
enzymes (Inoue et al. 1987; Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides 
flanking the phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE 
chemistry are preserved while also retaining RNase H1 recognition. 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides 
(MOE-Gapmer).  The sequence of volanesorsen is shown. 
2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III mRNA as 
well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in several species, 
including human apoC-III transgenic mice, and other rodent and monkey models.  Treatment with 
volanesorsen also resulted in reduced VLDL and chylomicron TG and reduced postprandial TG in 
hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of treatment 
followed by up to a 20-week recovery period are complete.  The preclinical toxicology program for 
volanesorsen consists of single dose safety pharmacology studies in the monkey (cardiovascular) and 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive) 
A  G  C 
T
T 
C  T 
T G T
C C A G C
T T T A T 
Phosphorothioate 
Backbone 


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mouse (neurobehavioral and pulmonary assessment studies), in vitro and in vivo genetic toxicity 
assessment, repeat dose fertility and/or developmental reproductive toxicology studies in the mouse and 
rabbit and evaluation in the in vitro human Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with those 
expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects consistent with drug 
accumulation in tissues in rodents and monkeys, species-dependent proinflammatory response in rodents 
and monkeys and complement activation and reductions in platelet counts in the monkey.  In the mouse 
and monkey general toxicity studies, reduction of hepatic apoC-III mRNA (> 75%) was not associated 
with any findings that could be considered related to the pharmacologic inhibition of apoC-III for up to 39 
weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent species are 
most sensitive to the proinflammatory effects of antisense molecules.  Importantly, these effects on the 
heart were not observed in the monkey chronic toxicity studies even at the highest doses tested where 
drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to be 
rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by measurement 
of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) and was 
non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or embryo/fetal 
development in the mouse or rabbit reproductive toxicity studies.  In these studies, volanesorsen was 
detected in placental tissue but not in fetal tissue indicating that little, if any, drug was able to cross the 
placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in males and 47% in females) also did 
not affect fertility or cause untoward effects on embryo/fetal development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be found in the 
volanesorsen Investigator’s Brochure. 
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found in the 
volanesorsen Investigator’s Brochure.  A summary is included below. 
The clinical experience with volanesorsen includes clinical trials in healthy subjects, patients with 
hypertriglyceridemia, FCS, or familial partial lipodystrophy. Overall, 431 patients and healthy volunteers 
have taken part in the clinical development program, of whom 325 have received at least 1 dose of 
volanesorsen. Ninety-five (95) patients with FCS have been enrolled in studies, all showing clinically 
meaningful reductions in plasma triglyceride. Patients with FCS continue on treatment in the open-label 
extension (OLE) and triglyceride reductions persist at similar levels as reported in earlier studies.  
In the completed Phase 1 and Phase 2 studies, volanesorsen was well-tolerated and demonstrated a 
favorable safety profile. There was no clinical or laboratory evidence of drug-drug interactions despite 
many patients in the Phase 2 clinical trials receiving concomitant medications that are known to be 
associated with elevations in hepatic enzymes, such as fibrates and statins. There were no volanesorsen-
associated laboratory abnormalities suggestive of an effect on the renal (serum creatinine, proteinuria) or 
hepatic systems (alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin). There 


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was a reduction (mean reduction < 30%) in platelets in volanesorsen vs. placebo with mean nadirs for all 
doses remaining above the lower limit of normal (LLN). The most frequently reported adverse events 
(AEs) were mild, non-progressive events at the injection site. In Phase 2, a single serious adverse event 
(SAE) of secondary serum sickness-like reaction was reported as related to Study Drug. 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in fasting plasma 
apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline with 300 mg dose) with a 
very high degree of consistency of response between the different patient groups.  This includes healthy 
volunteers, patients with moderate to severe hypertriglyceridemia not on background TG-lowering 
therapy, patients with moderate to severe hypertriglyceridemia on a background stable fibrate therapy 
(Gaudet et al. 2015), patients with FCS, and patients with T2DM. In a Phase 2 study, 3 patients with FCS 
were treated with 300 mg/wk volanesorsen in an open-label fashion.  These patients had a mean baseline 
fasting TG level of 1,844 mg/dL and all 3 patients achieved TG levels below or close to 500 mg/dL 
during the treatment period out to Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute 
reduction in fasting TG in excess of 1,500 mg/dL (Gaudet et al. 2014). 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
In the completed pooled Phase 3 studies (ISIS 304801-CS6 (hereafter referred to as CS6) and ISIS 
304801-CS16 (hereafter referred to as CS16), the most common AEs associated with volanesorsen 
administration were tolerability at the injection site and platelet reductions. The majority of the injection 
site AEs were mild, none were severe, and the incidence appeared to decrease over time. No deaths have 
been associated with volanesorsen treatment to date. No cardiac toxicity was associated with volanesorsen 
treatment. There were no abnormal QTc findings and no study-drug related adjudicated major adverse 
cardiac events (MACE). There is no evident association between volanesorsen treatment and changes in 
renal or liver functions. 


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The safety profile of volanesorsen has been well-described in this development program, which has 
identified 3 safety risks: thrombocytopenia (an identified risk), constitutional symptoms (flu-like 
reactions and influenza-like illness), and injection site reactions (a tolerability signal). Spontaneous, 
mild-to-severe thrombocytopenia has been described in the FCS patient population (Gaudet et al. 2017) 
but is increased by treatment with volanesorsen. Less frequent and less pronounced platelet declines were 
also observed with volanesorsen treatment in the hypertriglyceridemic (HTG) population of CS16. When 
fully complied with, frequent monitoring for this effect and appropriate dose adjustments have been 
successful both in preventing and promptly detecting the occurrence of severe platelet declines and often 
in retaining patients on treatment. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks, with the option of 
continuing treatment for up to an additional 104 weeks.  The dose of 300 mg per week and dose reduction 
of 300 mg every 2 weeks (delivered as a single 300 mg dose) are supported by both the cumulative 
nonclinical data available to date and the Phase 2 clinical data.  In nonclinical studies, volanesorsen 
treatment-related effects in rodents and monkeys were consistent with drug accumulation in tissues and 
also include species-specific proinflammatory responses.  In the monkey, the No-Observed-Adverse-
Effect Level (NOAEL) was defined by the cumulative clinical pathology results and histopathology data 
which provide an adequate clinical margin.  Non clinical findings were not considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 300 mg in 
patients with high triglycerides (including type 2 diabetes patients and administration in combination with 
fibrates and statins) with the most common AEs being local to the injection site and predominantly mild.  
A pooled analysis of safety for the Phase 2 studies did not demonstrate any clear difference in safety or 
tolerability between the different doses tested (100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, apoC-III, with 
a clear difference in the TG-lowering effect between the different doses in the 100 mg to 300 mg dose 
range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 2′-MOE-
modified ASOs that have been administered intravenously and subcutaneously in multiple clinical studies 
at doses up to 1200 mg and for treatment durations that exceed 24 months (Santos et al. 2015). 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 


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Following the Week 52 visit, patients will have the option to continue treatment for up to an additional 
104 weeks for a total of up to 156 weeks of treatment.  Patients not continuing treatment will enter a 
26-week post-treatment follow-up period.   
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Qualification 
A qualification period of up to 2 weeks (unless approved by the Sponsor) is given to complete 
qualification assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and 
Appendix A. 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for assessments at 
specified intervals throughout the 52-week treatment period as detailed in the Schedule of Procedures 
(Appendix A).  During the treatment period, volanesorsen is administered by subcutaneous (SC) injection 
once weekly. 
3.4.3 
Extended Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of continuing treatment 
for up to an additional 104 weeks.  Patients not continuing treatment will enter the 26-week 
post-treatment follow-up.  For patients that have entered the Extended Treatment Periods, study 
participation will be up to an additional 104 weeks or until commercialization of product, whichever is 
sooner. 
3.4.4 
Post-Treatment Follow-Up 
The post-treatment follow-up period is at least 26 weeks and consists of at least 9 Study Center visits. For 
patients not continuing into the 52-week extended treatment period, the post-treatment follow-up period 
visits will be conducted on Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 (Weeks 53, 54, 55, 56, 57, 58, 
and 71 may be conducted by a home healthcare nurse). 
For patients who have entered the first 52-week extended treatment period, but will not continue into the 
second 52-weeks of the extended treatment period, the post-treatment follow-up period visits will be 
conducted on Weeks 105, 106, 107, 108, 109, 110, 117, 123 and 130 (Weeks 105, 106, 107, 108, 109, 
110 and 123 may be conducted by a home healthcare nurse). 
For patients who have entered the second 52-week extended treatment period, the post-treatment follow-
up period visits will be on Weeks 157, 158, 159, 160, 161, 162, 169, 175 and 182 (Weeks 157, 158, 159, 
160, 161, 162 and 175 may be conducted by a home healthcare nurse). 


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3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, tolerability 
and efficacy data collected on volanesorsen during this study.  Based on its ongoing assessment of the 
safety and tolerability of volanesorsen, the DSMB will provide recommendations to the Sponsor for 
modifying, stopping or continuing the study as planned.  Details on the safety assessments, frequency of 
review and meeting schedules are outlined in the DSMB Charter and/or the statistical analysis plan 
(SAP). 
4.
PATIENT ENROLLMENT
4.1 
Qualification
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s written 
independent ethics committee/institutional review board (IEC/IRB) approval of the protocol, informed 
consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-specific 
procedures or evaluations related to this open-label study are performed.   
During the qualification period, the eligibility of the patient to enroll in the open-label study will be 
determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may be used for 
qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or ISIS 304801-CS16 
index studies (unless approved by the Sponsor) is given to complete qualification.  Qualified patients will 
retain the unique patient identification number that was assigned to them during the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies.  The patient identification number will be used to identify the patient 
throughout the extension trial and must be used on all study documentation related to that patient.  The 
patient identification number must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all qualification assessments have been 
completed and after the Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  
No patient may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY
To be eligible to participate in this study candidates must meet the following eligibility criteria within 2 
weeks of Study Day 1, or at the time point specified in the individual eligibility criterion listed. 
5.1 
Inclusion Criteria 
1.
Must give written informed consent to participate in the study (signed and dated) and any
authorizations required by law
2.
Age ≥ 18 years at time of informed consent


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3.
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index 
studies) with an acceptable safety profile, per Sponsor and Investigator judgement.
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the following criteria in 
order to enter into the open-label Study:
a.
History of chylomicronemia as evidenced by documentation of lactescent serum (a creamy 
top layer after ultracentrifugation of a fasting blood sample) or documentation of fasting TG 
measurement ≥ 880 mg/dL (10 mmol/L)
b.
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
supported by documentation of at least 1 of the following:
•
Confirmed homozygote, compound heterozygote or double heterozygote for known loss-
of-function mutations in Type 1-causing genes (such as LPL, apoC-II, GPIHBP1, or 
LMF1)
•
Post heparin plasma LPL activity of ≤ 20% of normal in medical history.  Note: testing of 
LPL activity should not be performed to confirm eligibility for the study.
c.
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 index study
4.
Able and willing to participate in a 78-week study
5.
Satisfy 1 of the following:
a.
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal (defined as 
12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 years, 
12 months of spontaneous amenorrhea without an alternative medical cause and follicle 
stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved), 
abstinent*, or if engaged in sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time of signing the informed 
consent form until 13 weeks after the last dose of Study Drug administration.
b.
Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of child-
bearing potential, patient is utilizing an acceptable contraceptive method (refer to
Section 6.3.1) from the time of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not
acceptable methods of contraception
5.2 
Exclusion Criteria 
1.
Diabetes mellitus with any of the following:
a.
Newly diagnosed within 12 weeks of Qualification
b.
HbA1c ≥ 9.0% at Qualification


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c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of Qualification [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of the 
Study (with the exception of ± 10 units of insulin) 
e. Current use of glucagon-like peptide-1 (GLP-1) agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to Qualification 
4. History within 6 months of Qualification of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack or 
unstable congestive cardiac failure requiring a change in medication or major surgery within 3 
months of Qualification 
5. Any of the following laboratory values at Qualification 
a. Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and documentation 
of Gilbert’s syndrome in which case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine dipstick.  In 
the event of a positive test eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on urine 
dipstick.  In the event of a positive test eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of Cockcroft-
Gault for estimation of glomerular filtration rate (GFR) in patients with low body weight 
after discussion with Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Qualification 
d. LDL-C > 130 mg/dL at Qualification 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the Sponsor, 
would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding diathesis or 
coagulopathy or clinically-significant abnormality in coagulation parameters at Qualification 
8. History of heart failure with NYHA greater than Class II 


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9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed 
prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or 
chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma 
in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1 month of 
Qualification, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and over-the-counter [OTC]), or fibrates unless on a 
stable dose for at least 3 months prior to Qualification and dose and regimen expected to 
remain constant during the treatment period.  Patients taking OTC omega-3 fatty acids should 
make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to Qualification 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Qualification  
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable dose 
for at least 3 months prior to Qualification and dose and regimen expected to remain stable 
throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
Qualification and dose and regimen expected to remain constant during the treatment period 
f. 
Glybera gene therapy within 2 years prior to Qualification 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on a stable 
dose for at least 4 weeks prior to Qualification and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to 
Qualification and dose and regimen expected to remain constant during the treatment period 
i. 
Plasma apheresis within 4 weeks prior to Qualification or planned during the study 
j. 
Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to Qualification (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of > 499 mL within 60 days 
of Qualification 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801) 
17. Have any other conditions, including new or worsening of existing condition, which, in the 
opinion of the Investigator or the Sponsor would make the patient unsuitable for inclusion, or 
could interfere with the patient participating in or completing the study 


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6.
STUDY PROCEDURES
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification  
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through the last 
patient’s Week 13 visit of the open-label study or until results from the database locks for the ISIS 
304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 5 times 
during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be administered once 
weekly (Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant medication/procedure 
information, lipid panel, blood viscosity, volanesorsen plasma concentrations, immunogenicity (IM) 
testing, platelet aggregation, liver/spleen magnetic resonance imaging (MRI), electrocardiograms 
(ECGs), echocardiograms and quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Adverse events at the injection site should be collected as adverse events.  
Dietary counseling will be reinforced at intervals throughout the treatment and follow-up period and all 
patients will complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 3, 4, 5, 6, 7, 
8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51 may be conducted by a home healthcare nurse.  Approval 
for study procedures to be conducted by a home healthcare nurse on other outpatient visit days will 
require prior approval by the Sponsor.  Patients must be fasted prior to drawing all blood samples and 
samples drawn locally should also be sent to the central laboratory for analysis whenever possible.  
Dosing instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined in 
Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent visits should 
be calculated based on the time elapsed since Day 1 rather than from the date of the previous visit. 
6.1.3 
Extended Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of continuing treatment 
for up to an additional 104 weeks.  For patients that have entered the Extended Treatment Periods, study 
participation will be up to an additional 104 weeks or until commercialization of product, whichever is 
sooner. 
During the extended treatment period, patients will have assessments and procedures done during Weeks 
54-156 as per the Schedule of Procedures in Appendix A.  Assessments and procedures may be conducted 
by either a home healthcare service or the Study Center, however the patient will be required to visit the 
study center approximately every 3 months.  Study Drug will be administered once weekly unless the 
patient is on a biweekly treatment schedule for safety reasons (Section 8.1).  Collection and measurement 
of vital signs, clinical laboratory parameters (including hematology, serum chemistry, and urinalysis), 


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AEs, concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, IM 
testing, ECGs, and physical examinations will be performed according to the Schedule of Procedures in 
Appendix A.  Adverse events at the injection site should be collected as adverse events.  Dietary 
counseling will be reinforced at intervals throughout the extended treatment period.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling will be conducted 
weekly and may be conducted by a home healthcare nurse.  Approval for study procedures to be 
conducted by a home healthcare nurse on other outpatient visit days will require prior approval by the 
Sponsor.  Patients must be fasted prior to drawing all blood samples and samples drawn locally should 
also be sent to the central laboratory for analysis whenever possible.  Treatment instructions and training 
will be provided to the patient where applicable. 
6.1.4 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup will have 
more frequent PK sampling over a 24-hour period following the first dose on Study Day 1 in order to 
evaluate the plasma PK parameters of volanesorsen.  Patients in this subgroup will have an additional 
visit to the clinic, or by a home healthcare nurse, on Day 2 to collect a 24-hour post-dose blood draw after 
treatment on Day 1.  The detailed PK sampling schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn for the 
subgroup-specific procedures (e.g., multiple blood draws for PK) without being withdrawn from the 
study.  If a patient withdraws consent from the subgroup procedures, he/she should remain on study and 
continue to follow all the non-subgroup assessments and procedures as outlined in Appendix A. 
6.1.5 
Post-Treatment Follow-up 
After completion of the Week 52 visit assessments, patients will have the option of continuing treatment 
for up to an additional 104 weeks as described in Section 6.1.3.  Patients not continuing treatment will 
enter the 26-week post-treatment follow-up.  For patients not continuing into the 52-week extended 
treatment period, the 26-week post-treatment follow-up period consists of at least 9 Study Center visits on 
Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 (Weeks 53, 54, 55, 56, 57, 58, and 71 may be conducted by a 
home healthcare nurse).  
For patients who enter the first 52-week extended treatment period, but will not continue into the second 
52-weeks of the extended treatment period, the post-treatment follow-up period visits will be conducted 
on Weeks 105, 106, 107, 108, 109, 110, 117, 123 and 130 (Weeks 105, 106, 107, 108, 109, 110 and 123 
may be conducted by a home healthcare nurse).  
For patients who enter the second 52-week extended treatment period, the post-treatment follow-up 
period visits will be on Weeks 157, 158, 159, 160, 161, 162, 169, 175 and 182 (Weeks 157, 158, 159, 
160, 161, 162 and 175 may be conducted by a home healthcare nurse). 
These visits are outlined in the Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is contained in 
Appendix B. 


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Each time a hematology lab is drawn and sent to the central laboratory for analysis, an additional sample 
should be collected in parallel and analyzed locally.  In the event that both the central and local sample 
are unreportable (e.g., due to hemolyzed or clumped blood samples), another sample must be repeated 
within 1 week and the result must be reviewed by the Investigator and confirmed to be acceptable before 
treatment can continue.  All platelet count results will be promptly reviewed by the Investigator to 
determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose 
pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
Should a patient experience constitutional or flu-like symptoms after Study Drug administration, 
investigators may consider additional laboratory assessments.  For example, plasma and serum samples 
may be drawn for complement (Total C3, C4, C5a and Bb), high-sensitivity C-reactive protein (hsCRP) 
and for cytokine analysis. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and body 
temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a sitting position 
for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should always be measured on 
the same arm (preferentially on the left arm).  Height will be measured at the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma since their 
last visit and the number/duration of the events will be recorded.  Physical exams should also include skin 
examination for presence/resolution of eruptive xanthomas.  If a patient experiences an episode of 
eruptive xanthoma during the study, photos of the area should be taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of the first 
dose of Study Drug (for ISIS 304801-CS16 roll over patients) and repeated at Week 52.  Images will be 
evaluated by an independent assessor, blinded to the patient’s treatment assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic valve 
function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of assessment of 
treatment-emergent changes, all echocardiograms will be evaluated on an ongoing basis by an 
independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 5 minutes.  
ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52.  During the post-
treatment follow-up, ECGs will be performed in triplicate at Weeks 65 and 78 for patients not opting to 
participate in the Extended Treatment Period.  Patients in the Extended Treatment Periods will have 
ECGs performed in triplicate at Weeks 76 and 104.  Triplicate ECGs will be performed at Weeks 13 and 
26 of each post-treatment follow-up period. 


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6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, Week 13, 
Week 26, and Week 52. During the post-treatment follow-up, patients will complete an EQ-5D and SF-36 
during Weeks 65 and 78. Should the patient enter the extended treatment periods, additional Quality of 
Life Questionnaires will be collected at Weeks 13 and 26 of each post-treatment follow-up period. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, Week 26, 
Week 52. During the post-treatment follow-up, patients will complete a 7-day food diary prior to 
Weeks 65 and 78. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient to 
provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, telephone 
calls from a dietitian or qualified study personnel to assess as to how each patient is maintaining 
their diet will be conducted randomly during the treatment and post treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior to 
screening and information relating to these events will be collected for independent adjudication.  
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and either 
be abstinent or, if engaged in sexual relations of child-bearing potential, practice effective contraception 
from the time of signing the informed consent form until at least 13 weeks after their last dose of study 
treatment. 


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Male patients must also encourage their female partner to use effective contraception from the time of 
signing the informed consent until 13 weeks after the subject’s last dose of study treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who has 
experienced menarche, and who does not meet 1 of the following conditions: 
• 
Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical 
cause and FSH levels in the postmenopausal range for the laboratory involved 
• 
6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• 
Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• 
Effective male contraception includes a vasectomy with negative semen analysis at follow-up, or 
the use of condoms together with spermicidal foam/gel/film/ cream/suppository.  Male patients 
must also encourage their female partner to use effective contraception from the time of signing 
the informed consent until 3 months after the patient’s last dose of study treatment.  Effective 
contraceptive for the female partner includes: surgical sterilization (e.g., bilateral tubal ligation), 
hormonal contraception, intrauterine contraception/device, or barrier methods (female condom*, 
diaphragm, sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  
Male patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• 
Using 1 or more of the following acceptable methods of contraception:  surgical sterilization 
(e.g., bilateral tubal ligation), hormonal contraception, intrauterine contraception/device, or any 2 
barrier methods (a combination of male or female condom* with diaphragm, sponge, or cervical 
cap) together with spermicidal foam/gel/film/cream/suppository. 
* Note: A female condom and a male condom should not be used together as friction between the two can 
result in either product failing. 
† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods 
of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours before 
visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 


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All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial and that 
serum lipase and/or amylase measures should be done in order to adjudicate the event, based on Atlanta 
Classification (Banks et al. 2013).  If serum or amylase activity is less than 3 x upper limit of normal 
(ULN), imaging, preferably contrast-enhanced computed tomography, should be considered to confirm 
the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7.
STUDY DRUG
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its storage 
and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen must be stored 
securely at 2 °C to 8 °C and be protected from light. 
Table 1  Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL 
Volume/Formulation 
1.5 mL solution per PFS 
Dose 
300 mg once weekly 
Route of Administration 
SC 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of volanesorsen 
provided by the Sponsor.  The Study Center must return all unused volanesorsen to the Sponsor or 
designee.  All used syringes must be disposed of as per the site’s hazardous waste destruction policy. 
8.
TREATMENT OF PATIENTS
8.1 
Volanesorsen Administration
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 300 mg 
injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on a reduced dose 
or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons in their index study 
(ISIS 304801-CS6 or ISIS 304801-CS16), will continue to receive Study Drug as a single 300 mg/1.5 mL 
injection once-weekly for Weeks 53-156 as outlined in Sections 8.5 and 8.6.  Patients on dose reduction 
will receive 300 mg/1.5 mL injections every 2 weeks.   
Patients should receive 1 dose per week, unless on a dose reduction of 300 mg every 2 weeks, with weeks 
always defined relative to Study Day 1.  For example, if a patient receives the first dose on a Monday, 
subsequent doses should be given on Mondays, if possible.  If a patient misses an injection, or if treatment 


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on the usual day is not possible, the patient can reschedule the injection provided that 2 doses are 
administered at least 2 days apart. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose assessment and 
the last measurement prior to Day 1 (e.g., qualification assessments or assessments from the final visits of 
ISIS 304801-CS6 and ISIS 304801-CS16 index studies if used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are provided 
for the monitoring of selected parameters chosen based on preclinical and clinical observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), the initial 
clinical laboratory results meeting the safety monitoring or stopping criteria presented below must be 
confirmed by performing measurements (ideally in the same laboratory that performed the initial 
measurement) on new specimens.  All new specimen collections should take place as soon as possible 
(ideally within 3 days of the initial collection).  For stopping rules, if the initial laboratory result is 
observed during the Treatment Period, the results from the retest must be available prior to administering 
the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request confirmation of 
additional lab values. 
Re-treatment Guidance:  Patients with initial laboratory test values that reach a stopping rule must not be 
re-dosed until the re-test results are available.  In general, patients who do not meet the stopping rules 
based upon retest may continue treatment.  However, the Investigator and the Sponsor Medical Monitor 
(or appropriately qualified designee) should confer as to whether additional close monitoring of the 
patient is appropriate.  Reduction in dose or dose frequency may also be initiated as noted in Section 8.7.  
If any of the stopping criteria described below (refer to Sections 8.6.1 to 8.6.3) are met, the patient will be 
dose paused or permanently discontinued (as described in the stopping criterion concerned) from further 
treatment with volanesorsen and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee and will be followed up in accordance with 
Section 8.8 of the protocol. 


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8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver Injury:  
Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human Services, Food 
and Drug Administration, July 2009.  For a definition of Baseline please refer to guidance in Section 8.5 
above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline value or 3 x 
ULN if the baseline value was > ULN) at any time during the study (Treatment or Post-Treatment 
Period), the initial measurement(s) should be confirmed as described above.  Additional confirmatory 
measurements should also be performed if ALT or AST levels increase to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or the 
greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their liver 
chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio (INR) and total 
bilirubin) retested at least once-weekly until ALT and AST levels become ≤ 1.2 x ULN or 1.2 x baseline 
value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST levels > 
3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN), the following 
evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV antibody 
panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or MRI 
scans, may be performed at the discretion of the Investigator, in consultation with the Sponsor Medical 
Monitor.  Repetition of the above evaluations should be considered if a patient’s ALT and/or AST levels 
reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3. 
Monitor every 1 week unless otherwise specified. In addition, platelet function may be evaluated at any 
time during the study by aggregometry, using an approved point-of-care diagnostic device, in some 
patients.  This additional functional testing may be performed at selected study centers. 
Study Drug administration is contingent on the availability of the immediately preceding test result.  An 
interpretable platelet value must be available within 7 days prior to treatment.  Only the study doctor or 
qualified designee can authorize continued Study Drug administration based on an acceptable platelet 
value.  Patients should not administer a dose until they have been contacted by their study doctor or 
designee and told that it is acceptable to dose.  Authorization to dose must be documented in the patient’s 
medical records. 


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Due to the 1 to 3-year study duration it is anticipated that patients may undertake travel including 
vacations, which may impede weekly platelet monitoring.  In some situations, it may be possible to 
arrange for local laboratory testing or use of the home healthcare service at their temporary location.  The 
intent is to maintain weekly platelet monitoring and treatment where possible, as well as Investigator site 
contact with the study patients.  However, if the above options are not possible, a temporary interruption 
of study treatment will be planned with a platelet count drawn within 3-5 days prior to departure and with 
a prompt blood draw upon the patient’s return which must be reported and reviewed by the Investigator 
prior to the patient resuming treatment. 
Patients on dose pause should be monitored as per the platelet monitoring rules outlined in Section 8.8.1 
until Study Drug administration is resumed. 
The tests outlined in Table 2 should also be performed as soon as possible.  Additional lab tests will be 
determined by the Sponsor Medical Monitor or designee in consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor (See 
also Stopping Rules Section 8.6.3). 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower Limit of 
Normal (×2) or < 100,000/mm3 (×1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) of platelet count less than the
lower limit of normal or who have any 1 occurrence of platelets < 100,000/mm3.  Labs only need to be
performed once.  Labs may be collected over multiple visits, if blood requirements are a concern, as per
investigator discretion.
Note: The following labs may change as additional data is assessed, and sites will be updated regarding
any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 


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Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-relevant, 
non-major bleeding events (which are defined in Section 8.6.3), for example excess bruising, petechiae, 
gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the Investigator must notify the 
Sponsor Medical Monitor and additional testing of coagulation parameters activated partial 
thromboplastin time (aPTT), prothrombin time (PT), INR and platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional symptoms 
that may arise during the study and the Investigator should closely evaluate all potential causes, including 
concomitant illness.  Patients that experience persistent constitutional symptoms should be discussed with 
the Sponsor Medical Monitor or designee to determine whether additional monitoring or laboratory tests 
are required. 
Should a patient experience constitutional or flu-like symptoms after Study Drug administration, 
investigators may consider additional laboratory assessments.  For example, plasma and serum samples 
may be drawn for complement (Total C3, C4, C5a and Bb), hsCRP and for cytokine analysis. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has a low-
density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with T2DM) on 
2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded for the remainder of 
the study and the Investigator will be encouraged to initiate/adjust treatment to lower LDL-C according to 
country-specific guidelines (e.g., initiate statin therapy or increase the statin dose for patients who are 
already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard practice 
guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In addition, patients 
who are not on insulin but use a glucometer should also bring their glucometer and/or glucometer log 
printout to every clinic visit. 
• 
The Investigator or delegate will review the glucometer reading or printout at every clinic visit to 
evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed threshold values as 
per the Safety Monitoring Rules for Hyperglycemia below. 


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All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, as well 
as any hypoglycemic episode they may experience. 
• 
The Investigator or delegate will ask patients at every clinic visit if they made changes in their 
insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic episodes at 
each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse events in the 
adverse event case report form (CRF). Documented symptomatic hypoglycemia is defined as 
typical hypoglycemia symptoms accompanied by measured plasma glucose ≤ 70 mg/dL (≤ 
3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as one in which the patient requires assistance of 
another person to obtain treatment for the event and has a plasma glucose level ≤ 70 mg/dL (≤ 3.9 
mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or buccal or intramuscular 
glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place patients at 
risk for injury to themselves or others.  Note that “requires assistance” means that the patient could not 
help himself or herself.  Someone being kind that assists spontaneously the patient when not necessary 
does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take immediate action 
to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are certain 
classical signs and symptoms, of which patients should be aware as a clue that their blood glucose may be 
low.  Common symptoms include headache, heart pounding, confusion, disorientation, numbness or 
tingling, pale skin, shakiness or tremulousness, increased appetite, anxiousness or nervousness, 
lightheadedness or dizziness, sweating, and weakness.  Coma could occur if blood sugar correction is not 
performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood glucose 
using their meters as soon as possible, before treatment if possible, provided they feel it is safe to do so.  
If there is doubt about safety they should treat the event first, using some sugar, milk, or juice for 
example, then obtain and record a blood glucose value as soon as possible thereafter.  The time and nature 
of treatment should be noted, and especially if any blood glucose result was before or after treatment.  It 
would be helpful for the patient to note if a contributory factor (e.g., missed or reduced meals, 
unaccustomed physical activity) occurred earlier in the day of the event. 


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8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be allowed during 
the course of the study, unless specific threshold values are met at Week 13 or later and confirmed on 
subsequent testing (ideally within 1 week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should self-
monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  If a fasting 
pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should check it again on the 
following 2 days.  If all the fasting pre-breakfast values on 3 consecutive days exceed the specific limit, 
the patient should contact the Investigator and an unscheduled central laboratory fasting plasma glucose 
(FPG) measurement and HbA1c should be performed. 
The threshold values are defined as: 
• 
FPG > 270 mg/dL (15.0 mmol/L) 
• 
HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 1% from 
baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that no 
reasonable explanation exists for insufficient glucose control and in particular that: 
• 
Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours fast) 
• 
Absence of intercurrent disease which may jeopardize glycemic control.  In case of an emergency 
(e.g., surgery, infection), the Investigator can take appropriate measures for glycemic control 
• 
Compliance to treatment is appropriate 
• 
Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator should 
consider the following: 
• 
Investigation and treatment of intercurrent disease (to be reported in adverse event 
(AE)/concomitant medication parts of the e-CRF) 
• 
Stress on the absolute need to be compliant to treatment 
• 
Organize a specific interview with a Registered Dietician or other qualified nutrition professional 
and stress on the absolute need to be compliant to diet and lifestyle recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  If none 
from the above-mentioned reasons can be found, or if appropriate action fails to decrease FPG/HbA1c 
under the threshold values, additional medication may be introduced at the Investigator’s discretion and 
according to local guidelines after discussion with the Sponsor Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, treatment with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued treatment and 
the need for any modification to treatment schedule (refer to Section 8.7) will be determined by the 
Investigator in consultation with the Study Medical Monitor. 


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8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose assessment and the 
last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an alternative 
explanation as discussed with the Sponsor Medical Monitor, treatment of a patient with volanesorsen 
will be stopped permanently; values that are not confirmed due to failure to retest or missing lab values 
will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), which is confirmed, and the new appearance (i.e., onset coincides with the changes in 
hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, or eosinophilia (> ULN) felt by the Investigator to be potentially related to hepatic 
inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 3 criteria 
below, treatment of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL (26.5 μmol/L) and 
≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault ≤ 40 
mL/min that is confirmed by a 24-hour urine collection 
The possible treatment re-initiation or follow-up schedule for any events meeting either of these criteria 
will be determined by the Investigator in consultation with the Sponsor Medical Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or clinically-
relevant non-major bleeding (defined below; Schulman et al. 2005), treatment of a patient with 
volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting this stopping 
criterion will be determined by the Investigator in consultation with the Sponsor Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a rate of decline ≥ 50% between two 
consecutive assessments, irrespective of the platelet level, or a platelet count less than 75,000/mm3 that 


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occurs while the patient is on treatment at 300 mg every 2 weeks, then treatment of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored as outlined in Table 3. 
Administration of steroids is recommended for patients whose platelet count is less than 50,000/mm3.  
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment 
guidelines for immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily 
for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or 
Methylprednisolone 30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after 
methylprednisolone).  In order to reduce the unlikely but potential increased risk of pancreatitis during the 
period of corticosteroid therapy, triglyceride levels will be monitored weekly, and AE monitoring will 
continue, during corticosteroid treatment and the laboratory alert will be changed from an increase of 
2,000 to 500 mg/dL during that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or clinically-
relevant non-major bleeding (defined below; Schulman et al. 2005), treatment of a patient with 
volanesorsen should be suspended temporarily until the platelet count has recovered to> 100,000/mm3.  If 
treatment is continued it should be at a reduced dose frequency of 300 mg every 2 weeks (refer to 
Section 8.7).  The suitability of the patient for continued treatment will be determined by the Investigator 
in consultation with the Study Medical Monitor and will be based on factors such as the original rate of 
decline in the patient’s platelet count, whether any bleeding events were experienced by the patient, and 
the speed of recovery of platelet count upon holding of treatment. 
If after the first treatment rechallenge the platelet count again falls below 75,000/mm3, then treatment of 
the patient with Study Drug will be stopped permanently. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
•
Fatal bleeding, and/or
•
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular,
retroperitoneal, intraarterial or pericardial, or intramuscular with compartment syndrome, and/or
•
Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 24 hours, or
leading to transfusion of 2 or more units of whole or red cells
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1.
Multiple-source bleeding
2.
Spontaneous hematoma > 25 cm2
3.
Excessive wound hematoma (not injection site related)
4.
Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an intervention)
5.
Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis
6.
Bleeding after venipuncture for > 5 minutes


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Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Study Drug administration is contingent on the 
availability of the immediately preceding test 
result.  An interpretable platelet value must be 
available within 7 days prior to treatment.  
Only the study doctor or qualified designee can 
authorize continued Study Drug administration 
based on an acceptable platelet value.  Patients 
should not administer a dose until they have 
been contacted by their study doctor or 
designee and told that it is acceptable to dose.  
Authorization to dose must be documented in 
the patient’s medical records. 
Monitor every 1 week unless 
otherwise specified 
In addition, platelet function may be 
evaluated during the study by 
aggregometry, using an approved 
point- of-care diagnostic device, in 
some patients.  This additional 
functional testing may be performed at 
selected study centers. 
Patients on dose pause should be 
monitored as per the platelet 
monitoring rules outlined in 
Section 8.8.1 until Study Drug 
administration is resumed. 
Obtain additional lab tests  
(Table 2) if 2 occurrences consecutive 
or non-consecutive of platelet count 
140K - > 100K/mm3 or 1 occurrence 
of platelet count ≤ 100K/mm3.  Labs 
only need to be performed once.  Labs 
may be collected over multiple visits, 
if blood requirements are a concern, as 
per Investigator discretion. 
> 100K/mm3 
Once weekly 300 mg Study Drug 
administration 
100K/mm3 - >75K/mm3 
Permanently reduce dose frequency to 300 mg 
every 2 weeks. 
75K/mm3 - >50K/mm3 
•
If occurs while on dose of 300 mg every
2 weeks, then permanently discontinue
Study Drug, otherwise dose pause. If
dose pause is ≥ 3 months then patient
must discontinue treatment and enter the
follow up period.
•
When platelet count returns to
> 100K/mm3 restart treatment at dose
frequency of 300 mg every 2 weeks in
consultation with the Sponsor Medical
Monitor
•
Monitor every 2-3 days until
2 successive values are
> 75K/mm3 then monitor every 1
week
•
Consider discontinuation of
antiplatelet agents/NSAIDS/
anticoagulant medication
< 50K/mm3 or a rate of decline ≥ 
50% between two consecutive 
assessments, irrespective of the 
platelet level 
Permanently discontinue Study Drug and the 
patient will enter the follow up period. 
• Monitor daily until 2 successive
values show improvement then
monitor every 2-3 days until
2 successive values are > 75K/mm3 
then monitor every 1 week
• Patient should be evaluated by a
hematologist to provide diagnostic
and therapeutic management
• Steroids recommended *.  It is
strongly recommended that, unless


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Platelet Count on Rx 
Drug Dose 
Monitoring 
the patient has a medical 
contraindication to receiving 
glucocorticoids, the patient receives 
glucocorticoid therapy to reverse the 
platelet decline.   
• Monitor triglyceride levels weekly 
and continue AE monitoring during 
steroid therapy  
• Discontinue antiplatelet agents/
NSAIDS/ anticoagulant medication 
while platelet count is< 50K/mm3 if 
possible. 
Legend: 
*
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for immune
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; 
Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days (note:  may require 
continuation with oral steroids after Methylprednisolone).  In order to reduce the unlikely but potential increased risk of 
pancreatitis during the period of corticosteroid therapy, triglyceride levels will be monitored weekly, and AE monitoring 
will continue, during corticosteroid treatment and the laboratory alert will be changed from an increase of 2,000 to 500 
mg/dL during that period. 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and Table 3 
(above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose frequency to 300 mg 
every 2 weeks will be allowed for safety and tolerability.  Any proposed adjustment to treatment schedule 
must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  Up to 
2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs, and the Study Medical Monitor is informed.  If a patient 
is dose paused for ≥ 3 months, he or she is considered to have discontinued treatment and should enter the 
26-week post-treatment follow-up period. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
•
The patient becomes pregnant.  Report the pregnancy according to instructions in Section 9.5.4
•
The patient withdraws consent
•
The patient experiences an AE that necessitates permanent discontinuation of study treatment
•
The patient develops laboratory test abnormalities that meet any of the stopping rules listed in
Section 8.6
•
The patient is dose paused for ≥ 3 months
The reason for discontinuation of study treatment must be recorded in the CRF and source documentation. 


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8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the platelet 
monitoring rules shown in Table 3 in Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  
Following this period, if the platelet count is stable (at least 3 consecutive values that are stable as 
determined by the Sponsor Medical Monitor and > 100,000/mm3), the next platelet count should be taken 
within at least 6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study 
Drug.  Any patient who discontinues treatment after Week 44 should also be strongly encouraged to 
attend a final follow-up visit (Week 78 visit assessments) approximately 26 weeks after their last dose of 
Study Drug. 
A patient who discontinues early from treatment with stable platelet counts above the LLN at the time of 
treatment discontinuation will have platelet counts drawn every 2 weeks after discontinuing Study Drug 
for the first 6 weeks after the last dose of Study Drug.  A subsequent platelet count should then be taken 
after an additional 6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study 
Drug. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and ideally 
within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up Period should 
be encouraged to follow the platelet monitoring rules shown in Table 3 in Section 8.6.3 for the first 6 
weeks after discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 3 
consecutive values that are stable as determined by the Sponsor Medical Monitor and > 100,000/mm3), 
the next platelet count should be taken within at least 6 weeks so that patients are monitored for at least 12 
weeks after discontinuing Study Drug.  Patients should also be encouraged to undergo a final follow-up 
visit (Week 78, see Appendix A) prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange for the 
patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
•
Withdrawal of consent
•
The patient is unwilling or unable to comply with the protocol
Other reasons for withdrawal of patients from the study might include: 
•
At the discretion of the Investigator for medical reasons
•
At the discretion of the Investigator or Sponsor for noncompliance
•
Significant protocol deviation
•
Commercialization of product


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All efforts will be made to complete and report the observations as thoroughly as possible up to the 
date of withdrawal.  All information, including the reason for withdrawal from study, must be recorded 
in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further treatment 
and study observation immediately upon the date of request.  These patients should be encouraged to 
complete the ET study procedures and observations at the time of withdrawal (see Section 8.8 and 
Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made to 
complete the early termination study procedures and observations at the time of withdrawal (see 
Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s CRF.  
AEs related to administration of these therapies or procedures must also be documented on the 
appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-counter 
medications, herbal medications and vitamin supplements) administered between signing informed 
consent and completion of the post-treatment follow-up period.  All concomitant medications/treatments 
and significant non-drug therapies (including supplements and assistive devices) received by a patient, 
including changes in the patient’s current medications, must be recorded in the patient’s source 
documents and CRF.  Patients taking over the counter (OTC) omega-3 fatty acids should make every 
effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the disallowed 
concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 fatty acids 
[including OTC preparations]), GLP-1 agonists, Glybera, or systemic corticosteroids may be started or 
adjusted after baseline Qualification.  Doses of existing oral anti-diabetic medication, oral contraceptives, 
hormone replacement therapy, anticoagulants, or drugs or dietary supplements with potential lipid-
altering effects should not be adjusted.  Study patients are prohibited from receiving other experimental 
agents during the study.  This includes marketed agents at experimental dosages that are being tested for 
the treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new medication, 
including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) or 
diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between signing of 


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informed consent and Week 78 (or Week 130 or 182 if the patient enters the first or second extended 
treatment period, respectively) visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment is to be monitored and recorded by Study Center staff.  The Study Center staff 
is required to document the receipt, dispensing, and return/destruction of volanesorsen.  Patients that are 
self-administering volanesorsen at home must record treatment in a treatment diary that will be reviewed 
periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with the 
Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of serious 
adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs) per the 
International Conference on Harmonization (ICH) guidelines E2A and ICH E6 (R2).  Country-specific 
regulatory requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any SAE 
according to applicable regulations.  The Independent DSMB will be notified of any SAE as specified in 
the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate the 
available information and perform an independent assessment of relatedness.  While the Sponsor may 
upgrade an Investigator’s decision it is not permissible to downgrade the Investigator’s opinion for the 
purposes of determining whether the SAE meets the definition of a SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an individual basis 
in an expedited manner because they are anticipated to occur in the study population independent of 
volanesorsen exposure.  The Investigator still has the responsibility to report all SAEs to the Sponsor as 
described in Sections 9.4.1 to 9.4.3.5. 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and the 
Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis acute, 
pancreatitis chronic, pancreatitis necrotizing, pancreatitis 
relapsing 
0.2-0.35 events per patient-year  
 


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Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The Sponsor and 
DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate of the event compared 
to the rate expected in a non-volanesorsen exposed population.  If the aggregate analysis indicates that an 
event is occurring significantly more frequently or at a greater severity than expected, then the event will 
be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether there is a 
reasonable possibility that the drug caused the event.  If the event is considered by the Sponsor or 
designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the study or use of 
investigational drug product, whether or not the AE is considered related to the investigational drug 
product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or Sponsor, meets 
any of the following criteria: 
• 
Results in death 
• 
Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not include 
an AE or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Hospitalization is defined as an admission of greater than 24 hours to a medical facility and does 
not always qualify as an AE 
• 
Results in a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Results in congenital anomaly or birth defect in the offspring of the patient (whether the patient is 
male or female) 
• 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may also be considered serious when, based upon appropriate medical judgment, 


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they may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the study 
(i.e., before informed consent) should be recorded as Medical History and not recorded as AEs unless the 
pre-existing condition worsened.  The Investigator should always group signs and symptoms into a single 
term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to volanesorsen) should be reported to the Sponsor or designee within 24 hours of the 
Study Center’s first knowledge of the event.  The collection of SAEs will begin after the patient signs the 
informed consent form and stop at the end of the patient’s follow-up period which is defined as the 
Week 78 (or Week 130 or 182 if the patient enters the first or second extended treatment period, 
respectively) visit.  When the Investigator is reporting by telephone, it is important to speak to someone in 
person versus leaving a message.  An Initial Serious Adverse Event Form should be completed and a copy 
should be faxed to the Sponsor or designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse Event Forms 
as soon as additional information becomes available.  All SAEs will be followed until resolution.  SAEs 
that remain ongoing past the patient’s last protocol-specified follow-up visit will be evaluated by the 
Investigator and Sponsor.  If the Investigator and Sponsor agree the patient’s condition is unlikely to 
resolve, the Investigator and Sponsor will determine the follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form and will 
stop at the end of the patient’s follow-up period, which is defined as the Week 78 (or Week 130 or 182 if 
the patient enters the first or second extended treatment period, respectively) visit.  The Investigator will 
monitor each patient closely and record all observed or volunteered AEs on the Adverse Event Case 
Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case Report 
Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• 
Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
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•
Possible:  The event cannot be explained by the patient’s medical condition, concomitant
therapy, or other causes, and there is a plausible temporal relationship between the event and
volanesorsen administration
•
Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g.,
concomitant medications or ongoing medical conditions) or the temporal relationship to
volanesorsen administration and/or exposure suggests that a causal relationship is unlikely (For
reporting purposes, Unlikely/Remote will be grouped together with Not Related)
•
Not Related:  The event can be readily explained by the patient’s underlying medical condition,
concomitant therapy, or other causes, and therefore, the Investigator believes no relationship
exists between the event and volanesorsen
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE not listed in 
Appendix D will be graded as follows: 
•
Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual daily
activities
•
Moderate:  The event causes the patient more discomfort and interrupts the patient’s usual daily
activities
•
Severe:  The event is incapacitating and causes considerable interference with the patient’s usual
daily activities
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
•
None:  No changes were made to volanesorsen administration and dose
•
Permanently Discontinued:  Volanesorsen was discontinued and not restarted
•
Temporarily Interrupted, restarted – same dose:  Treatment was temporarily interrupted or
delayed due to the AE and restarted at the same dose
•
Reduced schedule:  Treatment frequency was reduced
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the Adverse 
Event Case Report Form (treatment should also be recorded on the concomitant treatment or ancillary 
procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
•
AE Persists:  Patient terminates from the trial and the AE continues


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• 
Recovered:  Patient recovered completely from the AE 
• 
Became Serious:  The event became serious (the date that the event became serious should be 
recorded as the Resolution Date of that AE and the Onset Date of the corresponding SAE) 
• 
Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• 
Ongoing:  SAE continuing 
• 
Persists (as non-serious AE):  Patient has not fully recovered but the event no longer meets 
serious criteria and should be captured as an AE on the non-serious AE electronic Case Report 
Form (eCRF) (the SAE resolution date should be entered as the date of onset of that AE) 
• 
Recovered:  Patient recovered completely from the SAE (the date of recovery should be entered 
as the SAE resolution date) 
• 
Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event (MACE) 
will be adjudicated by a blinded, independent committee as outlined in the MACE Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute pancreatitis will 
be adjudicated by a blinded, independent committee according to the Atlanta classification of acute 
pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis Adjudication Charter.  In addition, data 
for prior episodes of acute pancreatitis or suspected pancreatitis will be collected by review of each 
patient’s medical chart and these events will also be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, constitute or 
be associated with an AE.  Examples of these include abnormal laboratory results that are associated with 
symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, tetany due to hypocalcemia, or 
cardiac arrhythmias due to hyperkalemia.  Whenever possible, the underlying diagnosis should be listed 
in preference to abnormal laboratory values as AEs.  Clinically-significant abnormalities will be 
monitored by the Investigator until the parameter returns to its baseline value or until agreement is 
reached between the Investigator and Sponsor Medical Monitor.  Laboratory abnormalities deemed not 
clinically-significant (NCS) by the Investigator should not be reported as AEs.  Similarly, laboratory 
abnormalities reported as AEs by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed clinical 
laboratory reports will serve as source documents and should include the Investigator’s assessment of 
clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered an SAE, 
even if the patient is hospitalized; the Study Center must document all of the following: 


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• 
The prescheduled or elective procedure or routinely scheduled treatment was scheduled (or was 
on a waiting list to be scheduled) prior to obtaining the patient’s consent to participate in the 
study 
• 
The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the Investigator 
between the patient’s consent to participate in the study and the timing of the procedure or 
treatment 
• 
The prescheduled or elective procedure or routinely scheduled treatment is the sole reason for the 
intervention or hospital admission 
9.5.3 
Treatment Errors 
Volanesorsen treatment errors should be documented as Protocol Deviations.  A brief description should 
be provided in the deviation, including whether the patient was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
Treatment details should be captured on the Treatment Case Report Form.  If the patient takes a dose of 
volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the symptom(s) 
should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to Investigator’s 
section of the Investigator’s Brochure and contact the Sponsor or designee within 24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate contraception 
with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes that he 
has made someone pregnant during the study, then the Study Center staff must be informed immediately.  
An Initial Pregnancy Form should be submitted to the Sponsor or designee within 24 hours of first 
learning of the occurrence of pregnancy.  Follow-up information including delivery or termination is 
reported on Follow-up Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a pregnancy 
test will be performed.  The patient with a confirmed pregnancy will be immediately withdrawn from 
treatment with volanesorsen.  However, the patient will be encouraged to complete the post-treatment 
follow-up portion of the study to the extent that study procedures do not interfere with the pregnancy.  
Regardless of continued study participation, the study physician will assist the patient in getting 
obstetrical care and the progress of the pregnancy will be followed until the outcome of the pregnancy is 
known (i.e., delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the birth 
of a child, the Study Center and Sponsor may require access to the mother and infant’s medical records 
for an additional 8 weeks after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed until the 
outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous abortion).  If the 
pregnancy results in the birth of a child, the Study Center and Sponsor may request access to the 


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mother and infant’s medical records for an additional 8 weeks after birth.  Follow-up will be 
performed to the extent permitted by applicable regulations and privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the average of 
Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 analysis time point 
is at the end of Month 6 are defined as the average of Week 25 (Day 169) and Week 26 (Day 176) fasting 
assessments, and the values at the Month 12 analysis time point are defined as the average of Week 50 
(Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during the treatment period 
• 
Percent change and change from baseline in other fasting lipid measurements including total 
cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• 
Adverse events including adjudicated events of pancreatitis and MACE 
• 
Vital signs and weight 
• 
Physical examinations  
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 


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10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active Study Drug 
and have a baseline TG assessment.  The FAS represents the practically-feasible intent-to-treat (ITT) 
population as delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of volanesorsen 
and with no significant protocol deviations that would be expected to affect efficacy and PD assessments.  
The detailed criteria will be specified and finalized prior to the final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have at least 
1 post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  Group 1 (ISIS 
304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the baseline in this open-label 
study, which is defined as the average of Day 1 pre-dose assessment and the last measurement prior to 
Day 1 (e.g., qualification assessments or assessments from final visit of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or ISIS 
304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study baseline.  For 
patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, baseline will be the last 
non-missing assessment prior to the first dose of Study Drug.  Details will be provided in the SAP. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label study or 
after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are locked and unblinded.  
Both safety and efficacy information from this open-label study may be summarized during this interim 
analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be provided in the 
patient data listings.  Patient data listings will be presented for all patients enrolled into the study.  
Descriptive summary statistics including n, mean, median, standard deviation, standard error, interquartile 
range (25th percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and 
counts and percentages for categorical variables will be used to summarize most data by treatment group 
of the index studies for patients on active Study Drug in the ISIS 304801-CS6 or ISIS 304801-CS16 
index studies, and pooled treatment naïve group which includes patients on placebo in index studies.  
Where appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided tests 
with 5% Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will be 
assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK endpoints will be 
assessed in the PK Set as applicable. 


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10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by treatment 
group and overall.  The patient disposition will be summarized by treatment group and overall.  All 
patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group and 
overall. 
Patient incidence rates of AEs will be tabulated by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class, MedDRA preferred term, and treatment group of the index studies.  
Narratives of treatment-emergent deaths, serious and significant AEs, including early withdrawals due to 
AEs, will also be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all treatment-
emergent serious AEs, and all treatment-emergent serious AEs potentially related to Study Drug will be 
summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term and 
severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) with 
differential, coagulation panel, IM, complement etc., will be summarized by study visits by treatment 
group. 
These safety variables will also be presented as change and percent change from baseline over time after 
Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will be 
summarized by treatment group.  Response rate of patients with fasting plasma TG < 750 mg/dL or 
achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and Month 12 will be 
summarized.  Response analysis will also be conducted using a range of fasting plasma TG thresholds for 
determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be summarized 
by treatment group for other fasting lipid measures including non-HDL-C, apoB, HDL-C, apoA-1, 
VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association between 
changes in lipid parameters and total amount of drug received will be examined, as appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event rate, 
quality of life assessments, and comparison of other symptoms including eruptive xanthomas and lipemia 
retinalis will be summarized by treatment group. 


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Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be summarized 
using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be carried out 
on each individual patient data set using data collected in the open-label study from the intensive PK 
subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., steady-state PK), 
depending on their earlier treatment in the index studies (Group 1 and 2 patients).  On Week 1 Day 1 of 
the open-label study, patients who received placebo in the index study will receive the first treatment of 
volanesorsen (single-dose PK), while patients who received volanesorsen in the index studies had been on 
volanesorsen treatment for 12 months (ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK 
data collected from these patients reflect steady-state PK.  The maximum observed drug concentration 
(Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  
Area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration (CL0-
24h/F) will be calculated from CL0-24h/F = Actual Dose/AUC0-24h.  Mean residence time (MRT) from time 
zero to 24 hours after the SC administration will be calculated from the equation, MRT0-24h = AUMC0-24h 
/AUC0-24h, where AUMC0-24h is the area under the moment plasma concentration-time curve from time 
zero to 24 hours after the SC administration.  Other PK parameters, as appropriate, may be determined or 
calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM status.  
Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and results will 
be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not evaluable, and 
when applicable, titer of anti-volanesorsen antibodies) before, during, and after treatment with Study 
Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be listed by their prior treatment 
in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subject ADA status 
(positive/negative or not evaluable) for all evaluable patients, along with the study day associated with the 
first positive IM status emerged (Tfirst, i.e., onset of ADA development), the last positive IM status 
observed (Tlast), the last ADA sample collection day, and subject - peak titer if applicable, will be listed by 
their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  
Subjects with positive anti-volanesorsen antibody status may be further classified (when applicable) as 
being either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, positive, and 
unknown status by treatment group.  Furthermore, onset and titer of the ADA response, if applicable, will 
be summarized as median, quartiles (25% and 75%), and range. 


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Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy (e.g., 
% change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK (e.g., Ctrough) 
measures will be evaluated using graphical analysis and statistical analysis.  These analyses will be either 
conducted and included in the study report, or data pooled and analyzed from all available Phase 2 and 
3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential patient 
population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written informed 
consent from the patient after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study and before any protocol-specific qualification procedures or any Study 
Drug are administered.  The patient must be given sufficient time to consider whether to participate in the 
study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her primary care 
physician should be documented in the patient’s medical records and the informed consent form should 
be signed and personally dated by the patient and by the person who conducted the informed consent 
discussion (not necessarily an Investigator).  The original signed informed consent form should be 
retained in the Study Master File and in any other locations required by institutional policy, and a copy of 
the signed consent form should be provided to the patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 2002 
the applicable regulations and guidelines of current Good Clinical Practice (GCP) as well as the demands 
of national drug and data protection laws and other applicable regulatory requirements will be strictly 
followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and any 
proposed advertising material must be submitted to the IEC/IRB for written approval.  A copy of the 
written approval of the protocol and informed consent form must be received by the Sponsor before 
recruitment of patients into the study and shipment of volanesorsen.  A copy of the written approval of 
any other items/materials that must be approved by the Study Center or IEC/IRB must also be received by 
the Sponsor before recruitment of patients into the study and shipment of Study Drug.  The Investigator’s 
Brochure must be submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The Investigator 
should notify the IEC/IRB of deviations from the protocol in accordance with ICH E6 (R2) Section 4.5.2.  
The Investigator should also notify the IEC/IRB of serious adverse events occurring at the Study Center 
and other adverse event reports received from the Sponsor, in accordance with local procedures. 


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The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout the 
duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the IEC/IRB 
continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report forms 
(CRF) or other documents submitted to the Sponsor, patients should be identified by unique initials and a 
patient study number only.  Documents that are not for submission to the Sponsor (e.g., signed informed 
consent forms) should be kept in strict confidence by the Investigator. 
In compliance with Federal and local regulations/ICH E6 (R2) Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IEC/IRB direct access to review the patient’s original medical records for verification of study-
related procedures and data.  Direct access includes examining, analyzing, verifying, and reproducing any 
records and reports that are important to the evaluation of the study.  The Investigator is obligated to 
inform and obtain the consent of the patient to permit named representatives to have access to his/her 
study-related records without violating the confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement from the 
Investigator must be obtained for all protocol amendments and amendments to the informed consent 
document.  The regulatory authority and IEC/IRB must be informed of all amendments and give approval 
for any amendments likely to affect the safety of the patients or the conduct of the trial.  The Investigator 
must send a copy of the approval letter from the IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  The 
Investigator reserves the right to terminate their participation in the study, according to the terms of the 
site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the trial’s completion or 
early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An eCRF utilizing an Electronic Data Capture (EDC) application will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has delegated trial 
duties are recorded on a Sponsor-approved Delegation of Site Responsibilities Form. 
Source documents are original documents, data, and records from which the patient’s CRF data are 
obtained.  These include but are not limited to hospital records, clinical and office charts, laboratory and 
pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs may not be used as source 
documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and centralized 
filing system of all study-related (essential) documentation in accordance with Section 8 of the ICH 
Guidelines E6 (R2), suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities.  Elements should include: 


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• 
Patient files containing completed CRFs, informed consents, and supporting copies of source 
documentation 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, copies of pre-
study documentation and all correspondence to and from the IEC/IRB and the Sponsor 
• 
If volanesorsen supplies are maintained at the Study Center, proof of receipt, volanesorsen 
Accountability Record, Return of volanesorsen for Destruction, final study volanesorsen 
reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and be 
readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or and the 
Investigator.  Should the Investigator wish to assign the study records to another party or move them to 
another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and visiting 
the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the various 
records of the trial (e.g., CRFs and other pertinent data) provided that patient confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to 
local regulations on the conduct of clinical research.  The monitor should have access to patient medical 
records and other study-related records needed to verify the entries on the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH E6 (R2) and the Sponsor’s audit plans, this study may be selected for audit by 
representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of Study Center 
facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-related records will occur 
to evaluate the trial conduct and compliance with the protocol, ICH E6 (R2), and applicable regulatory 
requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on patient data 
received by the Sponsor.  During this review, patient data will be checked for consistency, omissions, and 
any apparent discrepancies.  In addition, the data will be reviewed for adherence to the protocol and GCP.  
To resolve any questions arising from the clinical data management review process, data queries and/or 
Study Center notifications will be sent to the Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures will 
indicate that the principal Investigator inspected or reviewed the data on the CRF, the data queries, and 
the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications should be 
recorded in English if possible, unless it is a combination drug, then record the trade name in English. 


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All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow applicable local 
compensation laws.  Patients will be treated and/or compensated for any study-related illness/injury in 
accordance with the information provided in the Compensation for Injury section of the Informed Consent 
document.


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13. 
REFERENCES 
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to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Gaudet D, Baass A, Tremblay K, et al. Natural History (up to 15 years) of Platelet Count in 84 Patients with 
Familial Hyperchylomicronemia Due to Lipoprotein Lipase Deficiency. Journal of Clinical Lipidology 2017; 11(3): 
797-798. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 


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Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 
Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
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investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 


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Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
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with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
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14. 
APPENDICES 
 
 
 
Appendix A 
Schedule of Procedures 
 
Qualification through Treatment Period 
Post-Treatment Follow-up 
(For patients not opting to participate in the Extended Treatment Period) 
 
First 52-Week Extended Treatment Period 
First 52-Week Extended Treatment Period Post-Treatment Follow-Up 
(For patients not opting to participate in the second 52-Week Extended Treatment Period) 
 
Second 52-Week Extended Treatment Period 
Second 52-Week Extended Treatment Period Post-Treatment Follow-Up 
 


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Appendix A 
Schedule of Procedures – Qualification through Treatment Period 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
Xj 
Xj 
X
j 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight (+ height on Day 1 only) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
Xk 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
CBC with Differentialb 
X 
 X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
Serum Lipid Panel 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Blood viscosityr 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Platelet aggregationr 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Coagulation (aPTT, PT, INR) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
Xn 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Plasma PK - Volanesorsen 
 
Xl 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
FSH (women only, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Archived Serum & Plasma Samplese 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Troponin Io 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Bound Autoantibodiesr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archive blood sample for potential gene sequencing 
related to hypertriglyceridemia (Group 2 if not available 
from index study)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A 
Schedule of Procedures - Qualification through Treatment Period Continued 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to -1 
Wk 
1 
W
k 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to 
 -7 
1 
2 
22 
36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Urinalysisc 
X 
Xm 
 
X 
 
X 
 
 
Xm 
 
Xm 
 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Genetic testing for FCS diagnosis (if not 
available in medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Food/Drink Diary (quarterly)h 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Diet/Alcohol Counselingi 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Appendix A 
Schedule of Procedures – Post-Treatment Follow-up (for patients not opting to participate 
in the Extended Treatment Period) 
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 
540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Outpatient Visit 
Xj 
Xj 
X 
Xj 
X 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
Blood Draw (Fasting)c 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialb 
Xs 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
Serum Pregnancy Testd 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplese 
 
 
X 
 
X 
Urinalysisc 
 
Xm 
Xm 
Xm 
Xm 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Legend: 
a 
Qualification procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in 
parallel and analyzed locally.  In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or 
clumped blood samples) another sample must be repeated within 1 week and the result must be reviewed by the Investigator and 
confirmed to be acceptable before treatment can continue.  All platelet count results will be promptly reviewed by the 
Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule 
of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During 
treatment period urine and blood samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK 
blood draw. 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events 
(e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of kidney function, measurement of 
antibodies, etc.) in this or subsequent clinical studies of volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 ISIS 
304801-CS16 roll over patients) and repeated at Week 52 (Please refer to Section 6.2.2.2) 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
83 
g 
Genetic testing can be conducted for study Qualification (Group 2 ISIS 304801-CS16 roll over patients); genetic testing will only 
be conducted if allowed in the geographic region and only after the patient has given specific written informed consent for 
genetic testing. A blood sample for potential gene sequencing may be collected at timepoints other than Screening or 
Qualification Visits. 
h 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be 
performed by dietician or study personnel 
j 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study 
Center personnel 
k 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
l 
Full or abbreviated PK profile (see Appendix C) 
m 
Expanded urinalysis (see Appendix B) 
n 
HbA1c only 
o 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
p 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until apoC-III levels 
return to baseline values 
q 
Patient charts will be reviewed in order to collect data for events of acute pancreatitis or suspected pancreatitis in the patient’s 
medical history.  Chart review may be conducted at any time during the study.  These events will be adjudicated in the same 
manner as for events of pancreatitis during the study 
r 
May be done.  Blood viscosity and platelet aggregation in volanesorsen-treatment naïve patients only 
s 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
84 
Appendix A 
Schedule of Procedures – First 52-Week Extended Treatment Period 
Study Period 
Extended Treatment Period 
Study Week 
Wk 54 
& 56 
Wk 
58 
Wk 60 
& 62 
Mo 15 
Wk 64 
Wk 66 
& 68 
Wk 
70 
Wk 72 
& 74 
Mo 18 
Wk 76 
Wk 78 
& 80 
Wk 
82 
Wk 84, 86, 
& 88 
Mo 21 
Wk 90 
Wk 92 
& 94 
Wk 
96 
Wk 98, 
100 & 
102 
Mo 24 
Wk 104 
Study Day 
372 & 
386 
400 
414 & 
428  
442 
456 & 
470 
484 
498 & 
512 
526 
540 & 
554 
568  582, 596 & 
610 
624 
638 & 
652 
666 680, 694 
& 708 
722 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Outpatient Visit 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Vital Signs (+ body weight) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urinalysis (including P/C ratio) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood Draw (Fasting)b 
Chemistry Panel 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC with Differentiala 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
Serum Lipid Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Troponin I 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Plasma PK - ISIS 304801c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Anti-ISIS 304801 Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum Pregnancy Testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Platelet Functiong 
                                                                                                       X 
May be assessed at various timepoints, visits do not have specified windows to allow flexibility of scheduling. 
Weekly Study Drug: SC Injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet/Alcohol Counselinge 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Legend: 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
85 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. In the event that 
both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 1 week and the result must be 
reviewed by the Investigator and confirmed to be acceptable before treatment can continue.  All platelet count results will be promptly reviewed by the Investigator to 
determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 
should be reported in an expedited fashion to the Sponsor 
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood samples will be 
collected prior to Study Drug administration 
c 
Abbreviated PK collection (see Appendix C) 
d 
Females of childbearing potential only 
e 
To reinforce compliance to the diet and alcohol restrictions 
f 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel  
g 
May be done 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
86 
Appendix A 
Schedule of Procedures – First 52-Week Extended Treatment Period Post-Treatment 
Follow-Up (For patients not opting to participate in the second 52 Week Extended 
Treatment Period) 
Study Period 
Post Treatment Follow-upa 
Study Week 
Wk 106 
& 
108 
Wk 
110 
Wk 
117 
Wk 
123 
Wk 
130 
Study Day 
736 
& 
750 
764 
813 
855 
904 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Outpatient Visit 
Xb 
Xb 
X 
Xb 
X 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
Blood Draw (Fasting)e 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialc 
Xd 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
Serum Pregnancy Testf 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplesg 
 
 
X 
 
X 
Urinalysis 
 
Xh 
Xh 
Xh 
Xh 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Legend: 
a 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until apoC-III 
levels return to baseline values 
 
b 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the 
Study Center personnel  
c 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected 
in parallel and analyzed locally.  In the event that both the central and local sample are unreportable (e.g., due to hemolyzed 
or clumped blood samples) another sample must be repeated within 1 week and the result must be reviewed by the 
Investigator and confirmed to be acceptable before treatment can continue.  All platelet count results will be promptly 
reviewed by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or 
the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 
d 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling 
e 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.   
f 
Females of childbearing potential only 
g 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse 
events (e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of kidney function, 
measurement of antibodies, etc.) in this or subsequent clinical studies of volanesorsen 
h 
Expanded urinalysis (see Appendix B) 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
87 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be 
performed by dietician or study personnel 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
88 
Appendix A 
Schedule of Procedures – Second 52-Week Extended Treatment Period 
Study Period 
Extended Treatment Period 
Study Week 
Wk 116 
Mo 30 
Wk 128 
Mo 33 
Wk 142 
Wk 156 
Study Day 
806 
890 
988 
1086 
Visit Window+/- Days 
2 
2 
2 
2 
Outpatient Visit 
X 
X 
X 
X 
Vital Signs (+ body weight) 
X 
X 
X 
X 
Physical Examination 
 
X 
 
X 
Urinalysis (including P/C ratio) 
X 
X 
X 
X 
Blood Draw (Fasting) b 
Chemistry Panel 
X 
X 
X 
X 
CBC with Differentiala 
Xe 
Platelets are assessed each calendar week, visits do not have 
specified windows to allow flexibility of scheduling. 
Serum Lipid Panel 
X 
X 
X 
X 
Serum Pregnancy Testc 
X 
X 
X 
X 
Anti-ISIS 304801 Antibodies 
 
 
 
X 
Weekly Study Drug: SC Injection 
X  
Diet/Alcohol Counselingd 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
Legend: 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected 
in parallel and analyzed locally. In the event that both the central and local sample are unreportable (e.g., due to hemolyzed 
or clumped blood samples) another sample must be repeated within 1 week and the result must be reviewed by the 
Investigator and confirmed to be acceptable before treatment can continue.  All platelet count results will be promptly 
reviewed by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or 
the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During 
treatment period urine and blood samples will be collected prior to Study Drug administration 
c 
Females of childbearing potential only 
d 
To reinforce compliance to the diet and alcohol restrictions 
e 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the 
Study Center personnel 
   


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
89 
Appendix A 
Schedule of Procedures – Second 52-Week Extended Treatment Period Post-
Treatment Follow-Up  
Study Period 
Post Treatment Follow-upa 
Study Week 
Wk 158 & 
160 
Wk 162 
Wk 169 
Wk 175 
Wk 182 
Study Day 
1100 & 
1114  
1128 
1177 
1219 
1268 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Outpatient Visit 
Xb 
Xb 
X 
Xb 
X 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
Blood Draw (Fasting)e 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialc 
Xd 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
Serum Pregnancy Testf 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplesg 
 
 
X 
 
X 
Urinalysis 
 
Xh 
Xh 
Xh 
Xh 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Legend: 
a 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until apoC-III 
levels return to baseline values 
 
b 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the 
Study Center personnel  
c 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected 
in parallel and analyzed locally.  In the event that both the central and local sample are unreportable (e.g., due to hemolyzed 
or clumped blood samples) another sample must be repeated within 1 week and the result must be reviewed by the 
Investigator and confirmed to be acceptable before treatment can continue.  All platelet count results will be promptly 
reviewed by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or 
the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 
d 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling 
e 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours  
f 
Females of childbearing potential only 
g 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse 
events (e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of kidney function, 
measurement of antibodies, etc.) in this or subsequent clinical studies of volanesorsen 
h 
Expanded urinalysis (see Appendix B) 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be 
performed by dietician or study personnel 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
90 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
91 
Appendix B 
List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be performed on 
stored samples to better characterize the profile of volanesorsen or other similar oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
Troponin I2 
• 
CK-MB2 
• 
Platelet Bound 
Autoantibodies3 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
• 
Blood viscosity3 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination4 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
Platelet Function 
• 
Platelet aggregation3 
• 
Platelet function5 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation purposes, 
stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay development and/or 
validation), or to assess other actions of volanesorsen with plasma constituents 
2 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
3 
May be done 
4 
Will be performed on abnormal findings unless otherwise specified 
5 
May be done using a point-of-care device on site 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
92 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
93 
Appendix C 
Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected prior to 
treatment, and at various times throughout the treatment and post-treatment follow-up period as noted in 
the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
Post-dose 
Pre-dose Pre-dose Pre-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on Study Day 1.  
Participation is optional 
 
PK Sampling Schedule – First 52-Week Extended Treatment Period 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Wk 
130 
Study Day 
D526 
D722 
D813 
D904 
Visit Window 
+/- Days 
2 
2 
7 
7 
Time Point 
Pre-dose  
Pre-dose 
Anytime 
Anytime 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
94 
PK Sampling Schedule – Second 52-Week Extended Treatment Period 
Week 
Wk 
169 
Wk 
182 
Study Day 
D1177 
D1268 
Visit Window +/- 
Days 
7 
7 
Time Point 
Anytime 
Anytime 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
95 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
96 
 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are based 
upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
97 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 10 
Protocol - France 
01 May 2019 
 
98 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 
 


Sponsor: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
      Collaborator: 
      Ionis Pharmaceuticals, Inc. 
      2855 Gazelle Court 
      Carlsbad, CA  92010 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801)
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 9 - France – 25 May 2018 
EudraCT No:  2015-003755-21 




ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
3 
 
Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 9 - France 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Key Sponsor Contact: 
 
 
Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Phone: 
Email: 
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court  
Carlsbad, CA 92010  
Date: 
25 May 2018  
Confidentiality Statement 
This document contains confidential information of Akcea Therapeutics, Inc., that must not be disclosed 
to anyone other than the recipient study staff and members of the independent ethics committee, 
institutional review board, or authorized regulatory agencies.  This information cannot be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Akcea Therapeutics, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to Patients 
with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 9 - France 
Date:  
 
25 May 2018 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An Open-
Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS)”, dated 25 May 2018, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on Good 
Clinical Practice E6 (R2). 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Akcea Therapeutics, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT .................................................................................................................... 9 
PROTOCOL SYNOPSIS ......................................................................................................................... 14 
STUDY DESIGN AND TREATMENT SCHEMA ................................................................................ 20 
STUDY GLOSSARY ................................................................................................................................ 21 
1. 
OBJECTIVES .............................................................................................................................. 23 
2. 
BACKGROUND AND RATIONALE ....................................................................................... 23 
2.1 
Overview of Disease .................................................................................................................. 23 
2.2 
Therapeutic Rationale ................................................................................................................ 24 
2.3 
Volanesorsen ............................................................................................................................. 25 
2.3.1 
Mechanism of Action ........................................................................................................ 25 
2.3.2 
Chemistry .......................................................................................................................... 26 
2.3.3 
Preclinical Experience ....................................................................................................... 26 
2.3.4 
Clinical Experience ........................................................................................................... 27 
2.4 
Rationale for Dose and Schedule of Administration ................................................................. 28 
3. 
EXPERIMENTAL PLAN ........................................................................................................... 29 
3.1 
Study Design ............................................................................................................................. 29 
3.2 
Number of Study Centers .......................................................................................................... 29 
3.3 
Number of Patients .................................................................................................................... 29 
3.4 
Overall Study Duration and Follow-up ..................................................................................... 29 
3.4.1 
Qualification ...................................................................................................................... 29 
3.4.2 
Treatment .......................................................................................................................... 30 
3.4.3 
Extended Treatment Period ............................................................................................... 30 
3.4.4 
Post-Treatment Follow-Up ................................................................................................ 30 
3.5 
End-of-Study ............................................................................................................................. 30 
3.6 
Data and Safety Monitoring Board ............................................................................................ 30 
4. 
PATIENT ENROLLMENT ........................................................................................................ 30 
4.1 
Qualification .............................................................................................................................. 30 
4.2 
Enrollment ................................................................................................................................. 31 
5. 
PATIENT ELIGIBILITY ........................................................................................................... 31 
5.1 
Inclusion Criteria ....................................................................................................................... 31 
5.2 
Exclusion Criteria ...................................................................................................................... 32 
6. 
STUDY PROCEDURES ............................................................................................................. 34 
6.1 
Study Schedule .......................................................................................................................... 34 
6.1.1 
Qualification ...................................................................................................................... 34 
6.1.2 
Treatment Period ............................................................................................................... 34 
6.1.3 
Extended Treatment Period ............................................................................................... 35 
6.1.4 
Pharmacokinetic (PK) Subgroup ....................................................................................... 35 
6.1.5 
Post-Treatment Follow-up ................................................................................................. 35 


ISIS 304801-CS7 
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Amendment 9 
Protocol - France 
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6.2 
Additional Study Assessments .................................................................................................. 36 
6.2.1 
Laboratory Assessments .................................................................................................... 36 
6.2.2 
Physical Exams and Vital Signs ........................................................................................ 36 
6.2.2.1 
Eruptive Xanthoma .................................................................................................... 36 
6.2.2.2 
Lipemia Retinalis ....................................................................................................... 36 
6.2.3 
Echocardiography .............................................................................................................. 36 
6.2.4 
ECG.....................................................................................................................................36 
6.2.5 
MRI.....................................................................................................................................37 
6.2.6 
Quality of Life Assessments .............................................................................................. 37 
6.2.7 
Disease Symptom Diary .................................................................................................... 37 
6.2.8 
Diet Monitoring ................................................................................................................. 37 
6.2.9 
Family History ................................................................................................................... 37 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) ............. 37 
6.3 
Restriction on the Lifestyle of Patients...................................................................................... 37 
6.3.1 
Contraception Requirements ............................................................................................. 37 
6.3.2 
Other Requirements ........................................................................................................... 38 
7.
STUDY DRUG ............................................................................................................................. 39
7.1 
Volanesorsen Description .......................................................................................................... 39 
7.2 
Packaging and Labeling ............................................................................................................ 39 
7.3 
Study Drug Accountability ........................................................................................................ 39 
8.
TREATMENT OF PATIENTS .................................................................................................. 39
8.1 
Volanesorsen Administration .................................................................................................... 39 
8.2 
Other Protocol-Required Drugs ................................................................................................. 40 
8.3 
Other Protocol-Required Treatment Procedures ....................................................................... 40 
8.4 
Treatment Precautions ............................................................................................................... 40 
8.5 
Safety Monitoring Rules ............................................................................................................ 40 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ................................................................... 40 
8.5.2 
Safety Monitoring for Platelet Count Results ................................................................... 41 
8.5.3 
Safety Monitoring for Minor Bleeding Events .................................................................. 43 
8.5.4 
Safety Monitoring for Constitutional Symptoms .............................................................. 43 
8.5.5 
Safety Monitoring for LDL-C Elevations ......................................................................... 43 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...................... 43 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia .............................................. 44 
8.5.8 
Safety Monitoring for Hyperglycemia .............................................................................. 44 
8.5.9 
Acute Pancreatitis .............................................................................................................. 45 
8.6 
Stopping Rules .......................................................................................................................... 45 
8.6.1 
Stopping Rules for Liver Chemistry Elevations ................................................................ 45 
8.6.2 
Stopping Rules for Renal Function Test Results ............................................................... 46 
8.6.3 
Stopping Rules for Platelet Count Results ........................................................................ 46 
8.7 
Adjustment of Dose Frequency ................................................................................................. 48 
8.8 
Discontinuation of Study Treatment.......................................................................................... 49 


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8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...................................... 49 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period ............. 49 
8.9 
Withdrawal of Patients from the Study ..................................................................................... 49 
8.10 
Concomitant Therapy and Procedures ....................................................................................... 50 
8.10.1 
Concomitant Therapy ........................................................................................................ 50 
8.10.2 
Concomitant Procedures .................................................................................................... 51 
8.11 
Treatment Compliance .............................................................................................................. 51 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................... 51 
9.1 
Sponsor Review of Safety Information ..................................................................................... 51 
9.2 
Regulatory Requirements .......................................................................................................... 51 
9.3 
Definitions ................................................................................................................................. 52 
9.3.1 
Adverse Event ................................................................................................................... 52 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ......................................................... 52 
9.3.3 
Serious Adverse Event (SAE) ........................................................................................... 52 
9.4 
Monitoring and Recording Adverse Events .............................................................................. 53 
9.4.1 
Serious Adverse Events ..................................................................................................... 53 
9.4.2 
Non-Serious Adverse Events ............................................................................................. 53 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ................................................ 53 
9.4.3.1 
Relationship to the Study Drug .................................................................................. 53 
9.4.3.2 
Severity ....................................................................................................................... 54 
9.4.3.3 
Action Taken with Volanesorsen ............................................................................... 54 
9.4.3.4 
Treatment Given for Adverse Event........................................................................... 54 
9.4.3.5 
Outcome of the Adverse Event .................................................................................. 54 
9.4.4 
Adjudication Committees .................................................................................................. 55 
9.5 
Procedures for Handling Special Situations .............................................................................. 55 
9.5.1 
Abnormalities of Laboratory Tests .................................................................................... 55 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ....................... 55 
9.5.3 
Dosing Errors .................................................................................................................... 56 
9.5.4 
Contraception and Pregnancy ............................................................................................ 56 
10. 
STATISTICAL CONSIDERATIONS ....................................................................................... 57 
10.1 
Study Endpoints ........................................................................................................................ 57 
10.1.1 
Efficacy Endpoints ............................................................................................................ 57 
10.1.2 
Safety Endpoints................................................................................................................ 57 
10.2 
Sample Size ............................................................................................................................... 57 
10.3 
Populations ................................................................................................................................ 58 
10.4 
Definition of Baseline ................................................................................................................ 58 
10.5 
Interim Analysis ........................................................................................................................ 58 
10.6 
Planned Methods of Analysis .................................................................................................... 58 
10.6.1 
Demographic and Baseline Characteristics ....................................................................... 59 
10.6.2 
Safety Analysis .................................................................................................................. 59 
10.6.3 
Efficacy Analysis .............................................................................................................. 59 


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10.6.4 
Pharmacokinetic and Immunogenicity Analysis ............................................................... 60 
10.6.4.1 
Pharmacokinetic Analysis .......................................................................................... 60 
10.6.4.2 
Immunogenicity Analysis ........................................................................................... 60 
11.
INVESTIGATOR’S REGULATORY OBLIGATIONS .......................................................... 61
11.1 
Informed Consent ...................................................................................................................... 61 
11.2 
Ethical Conduct of the Study ..................................................................................................... 61 
11.3 
Independent Ethics Committee/Institutional Review Board ..................................................... 61 
11.4 
Patient Confidentiality ............................................................................................................... 62 
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS .............................................................. 62
12.1 
Protocol Amendments ............................................................................................................... 62 
12.2 
Study Termination ..................................................................................................................... 62 
12.3 
Study Documentation and Storage ............................................................................................ 62 
12.4 
Study Monitoring ...................................................................................................................... 63 
12.5 
Language ................................................................................................................................... 64 
12.6 
Compensation for Injury ............................................................................................................ 64 
13.
REFERENCES ............................................................................................................................. 65
14.
APPENDICES .............................................................................................................................. 68
Appendix A 
Schedule of Procedures .............................................................................................. 68 
Appendix B 
List of Laboratory Analytes ....................................................................................... 77 
Appendix C 
Pharmacokinetic Sampling Schedule ......................................................................... 78 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities ................ 79 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics................................................................. 39 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower 
Limit of Normal (x2) or < 100,000/mm3 (x1)* ................................................................. 42 
Table 3 
Actions in Patients with Low Platelet Count .................................................................... 47 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and the 
Expected Incidence ........................................................................................................... 51 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .......................... 24 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ............................................... 26 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen ........................... 28 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
9 
 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 9 - France 
Amendment Date: 
25 May 2018 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol ISIS 304801-CS7 Amendment 8 dated 
10 April 2017:  
1. To prolong the extended treatment period an additional 52 weeks. 
Minor changes (not included in the list of changes below) have been made throughout the protocol to correct errors and/or to improve the overall 
clarity of the original protocol but these changes do not impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol, additions are indicated as underline and deletions are indicated as 
strikethrough: 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis: 
Study Design and 
Study Visit 
Schedule and 
Procedures 
 
3.1 Study Design 
 
3.4.3 Extended 
Treatment Period 
Following the Week 52 visit, patients will enter an at least 26-week post-treatment evaluation period or will 
participate in an expanded access program pending approval by the IRBs/IEC, and the appropriate regulatory 
authorities. have the option to continue dosing for up to an additional 52 weeks for a total of 104 weeks of 
dosing.  Patients not continuing dosing will enter a 26-week post-treatment follow-up period.  
To allow patients the option of 
continuing treatment with 
volanesorsen after completion of 
the 52-week open-label treatment 
period. 
Protocol Synopsis: 
Study Visit 
Schedule and 
Procedures 
o 
An at least 26-week post-treatment evaluation period Option to participate in an extended 
treatment period (up to an additional 52 weeks) 
o 
A 26-week post-treatment follow-up period  
To allow patients the option of 
continuing treatment with 
volanesorsen after completion of 
the 52-week open-label treatment 
period. For patients continuing 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
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25 May 2018 
 
10 
treatment up to 104 weeks, the 26-
week post-treatment follow-up 
period has been added for those 
patients also. 
Section 6.1.3 
Extended 
Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of continuing dosing for up to 
an additional 52 weeks. 
During the extended treatment period, patients will have assessments and procedures done during Weeks 54-104 
as per the Schedule of Procedures in Appendix A.  Assessments and procedures may be conducted by either a 
home healthcare service or the Study Center, however the patient will be required to visit the study center 
approximately every 3 months.  Study Drug will be administered once weekly unless the patient is on a biweekly 
dosing schedule for safety reasons (Section 8.1).  Collection and measurement of vital signs, clinical laboratory 
parameters (including hematology, serum chemistry, and urinalysis), AEs, concomitant medication/procedure 
information, lipid panel, volanesorsen plasma concentrations, IM testing, ECGs, and physical examinations will 
be performed according to the Schedule of Procedures in Appendix A.  Adverse events at the injection site 
should be collected as adverse events.  Dietary counseling will be reinforced at intervals throughout the extended 
treatment period.  All blood and urine samples should be collected prior to volanesorsen administration.  Blood 
sampling at Weeks 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 79, 
80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103 may be conducted 
by a home healthcare nurse.  Approval for study procedures to be conducted by a home healthcare nurse on other 
outpatient visit days will require prior approval by the Sponsor.  Patients must be fasted prior to drawing all 
blood samples and samples drawn locally should also be sent to the central laboratory for analysis whenever 
possible.  Dosing instructions and training will be provided to the patient where applicable. 
To outline the procedures to be 
performed during the extended 
treatment period and 26-week post 
follow up treatment period.  The 
extended treatment period provides 
additional volanesorsen dose 
exposure and patient safety 
evaluations. 
Section 6.1.5 
After completion of the Week 52 visit assessments, patients will have the option of continuing dosing for up to 
an additional 52 weeks as described in Section 6.1.3.  Patients not continuing dosing will enter the 26-week 
post-treatment follow-up.  After completion of the Week 52 visit assessments, patients will enter the at least 26-
week post-treatment evaluation period or will participate in an expanded access program pending approval by 
the IRBs/IEC, and the appropriate regulatory authorities.  The 26-week period post-treatment follow-up consists 
of at least 9 Study Center visits on Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 (Weeks 53, 54, 55, 56, 57, 58, 
and 71 may be conducted by a home healthcare nurse). An additional 26-week post-treatment follow-up occurs 
after the extended treatment period with at least 9 Study Center visits on Weeks 105, 106, 107, 108, 109, 110, 
117, 118, and 125 (Weeks 105, 106, 107, 108, 109, 110, and 118 may be conducted by a home healthcare nurse. 
These visits, as are outlined in the Schedule of Procedures in Appendix A. 
To outline the procedures to be 
performed during the extended 
treatment period and 26-week post 
follow up treatment period. 


ISIS 304801-CS7 
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25 May 2018 
 
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Appendix A 
Schedule of 
Procedures—Post-
Treatment Follow-
Up 
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
W
k 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 449 49
1 
540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Informed Consent 
 
 
 
 
 
Outpatient Visit 
X
j 
X
j 
X 
Xj 
X 
Inclusion/Exclusion Criteria 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
Echocardiography 
 
 
 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialb 
X
s 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
Serum Pregnancy Testd 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplese 
 
 
X 
 
X 
Urinalysisc 
 
X
m 
X
m 
Xm 
Xm 
Fundus Photographyf 
 
 
 
 
 
Genetic testing for FCS diagnosis (if not available in medical history)g 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
X 
Removed assessments that were not 
conducted during the post-
treatment follow-up. 


ISIS 304801-CS7 
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12 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Appendix A: 
Schedule of 
Procedures—
Extended 
Treatment Period 
A Schedule of Procedures table was added for the 52 week extended treatment period.  
Schedule of procedures table added 
for the 52-week extended treatment 
period. 
Appendix A: 
Schedule of 
Procedures—
Extended 
Treatment Period 
Post-Treatment 
Follow-Up 
Study Period 
Post Treatment Follow-upa 
Study Week 
Wk 106 
& 
108 
Wk 
110 
Wk 
117 
Wk 
123 
Wk 
130 
Study Day 
736 
& 
750 
764 
813 
855 
904 
Visit Window+/- Days 
2 
7 
7 
7 
7 
 
 
 
 
 
 
Outpatient Visit 
Xb 
Xb 
X 
Xb 
X 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
Blood Draw (Fasting)e 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialc 
Xd 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated 
free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
Serum Pregnancy Testf 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplesg 
 
 
X 
 
X 
Urinalysis 
 
Xi 
Xi 
Xi 
Xi 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Schedule of procedures table added 
for 26 week post treatment follow-
up subsequent to the 52 week 
extended treatment period. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
13 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Appendix C: 
Pharmacokinetic 
Sampling 
Schedule 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Study Day 
D526 
D722 
D813 
Visit 
Window +/- 
Days 
2 
2 
7 
Time Point 
Pre-dose  
Pre-
dose 
Anytime 
A PK sampling scheduled was 
added for the 52 week extended 
treatment period. 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
14 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with volanesorsen 
(volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  Dietary 
counseling will be reinforced at intervals throughout the treatment and follow-up 
period.  Following the Week 52 visit, patients will have the option to continue dosing 
for up to an additional 52 weeks for a total of 104 weeks of dosing.  Patients not 
continuing dosing will enter a 26-week post-treatment follow-up period.  
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed and 
dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-
CS16 (index studies) with an acceptable safety profile, per Sponsor and 
Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the 
following criteria in order to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of lactescent 
serum (a creamy top layer after ultracentrifugation of a fasting blood 
sample) or documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of the 
following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-causing 
genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical 
history.  Note:  testing of LPL activity should not be performed to 
confirm eligibility for the study 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-
CS16 index study  
4. 
Able and willing to participate in a 78-week study 
Inclusion Criteria: Continued 
Study Population Continued 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
15 
Inclusion Criteria: Continued 
5.
Satisfy 1 of the following:
a.
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal
occlusion, hysterectomy, bilateral salpingectomy, bilateral
oophorectomy), post-menopausal (defined as 12 months of spontaneous
amenorrhea in females > 55 years of age or, in females ≤ 55 years, 12
months of spontaneous amenorrhea without an alternative medical cause
and FSH levels in the postmenopausal range for the laboratory involved),
abstinent*, or if engaged in sexual relations of child-bearing potential,
patient is using an acceptable contraceptive method (refer to
Section 6.3.1) from time of signing the informed consent form until 13
weeks after the last dose of Study Drug administration
b.
Males:  Surgically sterile, abstinent* or if engaged in sexual relations
with a female of child-bearing potential, patient is utilizing an acceptable
contraceptive method (refer to Section 6.3.1) from the time of signing the
informed consent form until 13 weeks after the last dose of Study Drug
administration
* Abstinence is only acceptable as true abstinence, i.e., when this is in line
with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial and withdrawal are not acceptable 
methods of contraception 
Exclusion Criteria: 
1.
Diabetes mellitus with any of the following:
a.
Newly diagnosed within 12 weeks of Qualification
b.
HbA1c ≥ 9.0% at Qualification
c.
Recent change in anti-diabetic pharmacotherapy (change in dosage or
addition of new medication within 12 weeks of Qualification [with the
exception of ± 10 units of insulin])
d.
Anticipated need to change dose or type of medication during the treatment
period of the Study (with the exception of ± 10 units of insulin)
e.
Current use of GLP-1 agonists
2.
Severe hypertriglyceridemia other than due to familial chylomicronemia
syndrome
3.
Active pancreatitis within 4 weeks prior to Qualification
4.
History within 6 months of Qualification of acute or unstable cardiac ischemia
(myocardial infarction, acute coronary syndrome, new onset angina), stroke,
transient ischemic attack or unstable congestive cardiac failure requiring a
change in medication or major surgery within 3 months of Qualification


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
16 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
5. Any of the following laboratory values at Qualification 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which case 
total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein 
on urine dipstick.  In the event of a positive test eligibility may be 
confirmed by a quantitative total urine protein measurement of 
< 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace positive) 
for blood on urine dipstick.  In the event of a positive test 
eligibility may be confirmed with urine microscopy showing ≤ 5 
red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the formula 
of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault for 
estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Qualification 
d. 
LDL-C > 130 mg/dL at Qualification 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding 
diathesis or coagulopathy or clinically-significant abnormality in coagulation 
parameters at Qualification 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will 
not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the 
skin or carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1 
month of Qualification, or 5 half-lives of investigational agent, whichever is 
longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
14. Use of any of the following:
a.
Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a
stable dose for at least 3 months prior to Qualification and dose and regimen
expected to remain constant during the treatment period.  Patients taking
OTC omega-3 fatty acids should make every effort to remain on the same
brand throughout the study
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to
Qualification
c.
Systemic corticosteroids or anabolic steroids within 6 weeks prior to
Qualification unless approved by the Sponsor Medical Monitor
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on
a stable dose for at least 3 months prior to Qualification and dose and
regimen expected to remain stable throughout the study
e.
Antihypertensive medication unless on a stable dose for at least 4 weeks
prior to Qualification and dose and regimen expected to remain constant
during the treatment period
f.
Glybera gene therapy within 2 years prior to Qualification
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban)
unless on a stable dose for at least 4 weeks prior to Qualification and regular
clinical monitoring is performed
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4
months prior to Qualification and dose and regimen expected to remain
constant during the treatment period
i.
Plasma apheresis within 4 weeks prior to Qualification or planned during the
study
j.
Prior exposure to ISIS 304801
k. Any other medication unless stable at least 4 weeks prior to Qualification
(Occasional or intermittent use of over-the-counter medications will be
allowed at Investigator’s discretion)
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of > 499 mL
within 60 days of Qualification
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801
or placebo)
17. Have any other conditions, including new or worsening of existing condition,
which, in the opinion of the Investigator or the Sponsor would make the patient
unsuitable for inclusion, or could interfere with the patient participating in or
completing the study
Treatment Group 
Volanesorsen 300 mg once per week 
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose frequency 
will be allowed for safety or tolerability after consultation with the Sponsor Medical 
Monitor. 


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PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and ISIS 304801-CS16) 
based on the pharmacodynamic and safety analysis of the Phase 2 studies 
(Section 2.4) which included a subset of patients with FCS.  The same dose of 300 
mg once weekly will be used in this open-label study of FCS patients.  
Study Visit Schedule and Procedures The study for an individual patient will generally consist of the following periods: 
• 
A qualification period of up to 2 weeks (unless approved by the Sponsor).  
Please refer to Section 4.1 and Appendix A 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
Option to participate in an extended treatment period (up to an 
additional 52 weeks) 
o 
A 26-week post-treatment follow-up period  
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid 
data through the last patient’s Week 13 visit of the open-label study or until results 
from the database locks for the ISIS 304801-CS6 and ISIS 304801-CS16 index 
studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), adverse events (AE), concomitant 
medication/procedure information, lipid panel, blood viscosity, volanesorsen plasma 
concentrations, immunogenicity (IM) testing, platelet aggregation, liver/spleen 
magnetic resonance imaging (MRI), ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in 
Appendix A.  Dietary counseling will be repeated at intervals throughout the 
treatment and follow-up period and a daily food/drink diary will be completed for the 
week prior to each quarterly visit by each patient.  Following the Week 52 visit, 
patients will have the option to continue dosing for up to an additional 52 weeks. 
Patients not to continuing dosing will enter a 26-week post-treatment follow-up 
period. 
Safety and Tolerability Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by determining the 
incidence and severity of adverse and serious adverse events (including 
independently adjudicated events of acute pancreatitis and MACE), withdrawals due 
to adverse events, and changes in laboratory and other safety parameters. 
 
 
 


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PROTOCOL SYNOPSIS Continued 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis and 
MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during the 
treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III (apoC-
III) 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of volanesorsen 
as follows: trough levels (pre-dose) throughout treatment and post-treatment levels 
during the post-treatment follow-up period.  In a subset of patients, more frequent 
assessment of plasma concentrations of volanesorsen will be performed to determine 
volanesorsen pharmacokinetic parameters.  Plasma sample collection time points are 
detailed in Appendix A and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Akcea Therapeutics, Inc. 
Collaborator 
Ionis Pharmaceuticals, Inc. 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at specified 
time points 
EXTENDED TREATMENT PERIOD 
Weeks 53 to 104 
Patients will have the option to continue 
dosing for up to an additional 52 weeks. 
 
 
POST-TREATMENT FOLLOW-UP 
Weeks 53 to 78* 
(Treatment Period Post Treatment 
Follow-Up) 
 
And Weeks 105 to 130 
(Extended Treatment Period Post 
Treatment Follow-Up) 
 
Safety, efficacy, PK and PD assessments 
* If needed, the post-treatment follow-up 
period will be extended (with patients 
monitored every 6 weeks) until apoC-III 
levels return to baseline values 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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Abbreviation/Acronym 
Definition 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 


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1.
OBJECTIVES
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen in patients with familial chylomicronemia syndrome. 
2.
BACKGROUND AND RATIONALE
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare autosomal 
recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above normal 
(1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 15-20% of daily 
calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in infancy or childhood with 
frequent and severe abdominal pain, repetitive colicky pain, repeated episodes of potentially fatal acute 
pancreatitis, and failure to thrive (Brunzell 1999-2011; Tremblay et al. 2011).  Physical examination 
frequently reveals eruptive xanthomas, lipemia retinalis and hepatosplenomegaly, and plasma from 
patients appears lactescent, interfering with determination of other laboratory parameters (Tremblay et al. 
2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of chylomicronemia.  
Clinical diagnosis would include evidence of clinical features of chylomicronemia syndrome and 
secondary causes such as uncontrolled type 1 or type 2 diabetes mellitus (T2DM), hypothyroidism, poor 
diet, alcohol use, nephrotic syndrome or use of associated medications should be ruled out.  The diagnosis 
of FCS may be made more specifically by genotyping or confirmation of very low or absent lipoprotein 
lipase (LPL) enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described above, 
being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent episodes of 
acute pancreatitis, these patients may also develop chronic pancreatitis and signs of exocrine or endocrine 
pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  While the pathophysiology 
underlying chylomicron-related pancreatitis has not been completely elucidated, 1 hypothesis is that large 
chylomicrons lodged in pancreatic capillaries are exposed to pancreatic lipase, with the subsequent 
release of free fatty acids through the hydrolysis of chylomicron-associated TGs.  High concentrations of 
free fatty acids are thought to damage pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; 
Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, skeletal 
muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL is regulated by a 
number of key genes, and loss-of-function mutations in one of these genes, or the LPL gene itself, results 
in FCS (Surendran et al. 2012).  In addition to loss of function mutations, null mutations, and nonsense 
mutations in the LPL gene, other genes currently identified in FCS patients, and known to directly 
influence LPL activity include: apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); 
apolipoprotein A-V (APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 
1 (LMF1), a transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 


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glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary endothelial cell 
protein that provides a platform for LPL-mediated processing of chylomicrons (Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major regulator 
of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels (Chan et al. 2008).  It is 
a component of triglyceride-rich lipoproteins (TRLs) and a potent inhibitor of LPL (Lemieux et al. 2003).  
At higher concentrations apoC-III also inhibits hepatic lipase activity (Kinnunen and Ehnolm 1976), an 
enzyme which plays an important role in the conversion of dense very-low-density lipoprotein (VLDL) to 
intermediate density lipoprotein (IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of 
HDL (Brown et al. 2010).  In addition, increased apoC-III content adversely affects apoE-mediated 
hepatic uptake of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are 
associated with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the development of 
hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 
Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in inhibiting LPL, 


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apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by hepatic lipoprotein receptors 
by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or nonsense 
mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; Pollin et al. 2008; 
Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was identified in the heritability 
and phenotype intervention (HAPI) heart study in Old Order Amish that results in lower plasma apoC-III 
and TG levels and lower LDL-C, increased HDL-C and reduced atherosclerosis (Pollin et al. 2008).  In 
another study involving a group of 214 Ashkenazi Jews of advanced age (had passed or nearly reached 
100 years of age), genotype analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC 
genotype) with a clear pattern of age-dependent frequency that was associated with significantly lower 
levels of apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  
In contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, apoC-
III polymorphisms associated with higher plasma TG have also been recently described (Petersen et al. 
2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) Asian Indians, carriers of 
apoC-III variant alleles (C-482T, T-455C, or both) were noted to have significantly higher plasma apoC-
III and TG levels, and decreased ability to clear postprandial plasma TG from the circulation.  Taken 
together, the available data strongly support the development of a therapy that reduces plasma apoC-III 
levels in order to reduce the very high circulating triglyceride and chylomicron levels that are 
accompanied by increasing risk for acute pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients who have no 
detectable LPL activity (See Section 2.3.4), and the mechanistic data available to date on apoC-III 
function, potential mechanisms that explain how apoC-III inhibition results in triglyceride reduction in 
FCS patients include:  (1) enhancing the very small residual amounts of LPL activity that these patients 
may have, below the limit of detection of the assay in many cases (2) potentially enhanced activity of 
other lipases also involved in the metabolism and breakdown of TGs, such as hepatic lipase or endothelial 
lipase (Kinnunen and Ehnolm 1976), and (3) apoC-III interaction with Apolipoprotein E (apoE), an 
important factor in liver reuptake of lipid particles by blocking apoE-mediated uptake of lipid particles in 
the liver (Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all of these 
mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential to 
manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human apoC-III.  It 
is complementary to a region within the 3ʹ untranslated region of the apoC-III messenger ribonucleic acid 
(mRNA) and binds to the mRNA by Watson and Crick base pairing.  The hybridization (binding) of 
volanesorsen to the cognate mRNA, results in the RNase H1-mediated degradation of the apoC-III 
mRNA, thus preventing production of the apoC-III protein.  Maximal antisense-mediated reduction of 
target mRNA levels is typically greater than 90% of control levels in sensitive tissues (Crooke and 
Bennett 1996; Zhang et al. 2010).  Furthermore, reduction in target mRNA levels using this approach 
correlates directly with a subsequent reduction in target protein levels. 


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2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are connected 
sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen (Figure 2) is 
complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the apoC-III mRNA 
transcript at base position 489-508.  Structurally, the oligonucleotide has 3 regions.  Two (2) of them, the 
5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are composed of 2ʹ-O-(2-methoxyethyl) 
(MOE)-modified ribonucleotides.  These MOE-modified nucleotides confer (1) increased affinity to the 
target mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of 
the high dose toxicities thereby resulting in an improved safety profile compared to first generation 
antisense drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 10 oligodeoxynucleotides.  
This chimeric design is called a MOE-Gapmer, and volanesorsen employs this chimeric structure to 
enable use of the RNase H1-mechanism for antisense activity.  This is because while the 2ʹ-MOE 
modification confers increased stability and affinity, it does not support RNase H1 catalysis of RNA 
hybridized to 2ʹ-MOE-modified nucleotides (McKay et al. 1999).  This is caused by conformational 
changes induced in the heteroduplex by 2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 
enzymes (Inoue et al. 1987; Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides 
flanking the phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE 
chemistry are preserved while also retaining RNase H1 recognition. 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides 
(MOE-Gapmer).  The sequence of volanesorsen is shown 
2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III mRNA as 
well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in several species, 
including human apoC-III transgenic mice, and other rodent and monkey models.  Treatment with 
volanesorsen also resulted in reduced VLDL and chylomicron TG and reduced postprandial TG in 
hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of treatment 
followed by up to a 20-week recovery period are complete.  The preclinical toxicology program for 
volanesorsen consists of single dose safety pharmacology studies in the monkey (cardiovascular) and 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive) 
A  G  C 
T
T 
C  T 
T G T
C C A G C
T T T A T
Phosphorothioate 
Backbone 


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mouse (neurobehavioral and pulmonary assessment studies), in vitro and in vivo genetic toxicity 
assessment, repeat dose fertility and/or developmental reproductive toxicology studies in the mouse and 
rabbit and evaluation in the in vitro human Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with those 
expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects consistent with drug 
accumulation in tissues in rodents and monkeys, species-dependent proinflammatory response in rodents 
and monkeys and complement activation and reductions in platelet counts in the monkey.  In the mouse 
and monkey general toxicity studies, reduction of hepatic apoC-III mRNA (> 75%) was not associated 
with any findings that could be considered related to the pharmacologic inhibition of apoC-III for up to 39 
weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent species are 
most sensitive to the proinflammatory effects of antisense molecules.  Importantly, these effects on the 
heart were not observed in the monkey chronic toxicity studies even at the highest doses tested where 
drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to be 
rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by measurement 
of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) and was 
non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or embryo/fetal 
development in the mouse or rabbit reproductive toxicity studies.  In these studies, volanesorsen was 
detected in placental tissue but not in fetal tissue indicating that little, if any, drug was able to cross the 
placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in males and 47% in females) also did 
not affect fertility or cause untoward effects on embryo/fetal development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be found in the 
volanesorsen Investigator’s Brochure. 
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found in the 
volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double blinded and 
placebo controlled.  The total exposures comprise 99 patients and healthy volunteers administered 
volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in fasting plasma 
apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline with 300 mg dose) with a 
very high degree of consistency of response between the different patient groups.  This includes healthy 
volunteers, patients with moderate to severe hypertriglyceridemia not on background TG-lowering 
therapy, patients with moderate to severe hypertriglyceridemia on a background stable fibrate therapy 
(Gaudet et al. 2015), patients with FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an open-label 
fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 3 patients achieved 


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TG levels below or close to 500 mg/dL during the dosing period out to Day 92 (Figure 3).  Two (2) of the 
FCS patients had an absolute reduction in fasting TG in excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a favorable 
safety profile.  There has been no clinical or laboratory evidence of drug-drug interactions. 
In the completed studies there have been no volanesorsen associated laboratory abnormalities suggestive 
of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there was a mild decrease of 
platelet count associated with volanesorsen administration that recovered in the post-treatment period and 
was not associated with platelet-related adverse events (AEs).  In the blinded ongoing clinical trials of 
ISIS 304801, 2 patients of 142 dosed (as of February 29, 2016) had a decrease in platelet count to less 
than 50,000/mm3 in the absence of major bleeding or clinically-relevant non-major bleeding and had 
Study Drug paused as per the monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet 
counts recovered following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  Local 
cutaneous reactions at the injection site defined as those events presenting as either pain, tenderness, 
erythema, pruritus or swelling occurring on the day of injection and persisting for at least 2 days were 
infrequent (~15% of injections), were almost always mild, resolved spontaneously, were non-progressive, 
and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks, with the option of 
continuing dosing for an additional 52 weeks.  The dose of 300 mg per week is supported by both the 
cumulative nonclinical data available to date and the Phase 2 clinical data.  In nonclinical studies, 
volanesorsen treatment-related effects in rodents and monkeys were consistent with drug accumulation in 


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tissues and also include species-specific proinflammatory responses.  In the monkey, the No-Observed-
Adverse-Effect Level (NOAEL) was defined by the cumulative clinical pathology results and 
histopathology data which provide an adequate clinical margin.  No nonclinical findings were considered 
to be related to the pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 300 mg in 
patients with high triglycerides (including type 2 diabetes patients and administration in combination with 
fibrates and statins) with the most common AEs being local to the injection site and predominantly mild.  
A pooled analysis of safety for the Phase 2 studies did not demonstrate any clear difference in safety or 
tolerability between the different doses tested (100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, apoC-III, with 
a clear difference in the TG-lowering effect between the different doses in the 100 mg to 300 mg dose 
range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 2′-MOE-
modified ASOs that have been safely administered intravenously and subcutaneously in multiple clinical 
studies at doses up to 1000 mg and for treatment durations that exceed 24 months (Santos et al. 2015). 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients will have the option to continue dosing for up to an additional 52 
weeks for a total of 104 weeks of dosing. Patients not to continuing dosing will enter a 26-week post-
treatment follow-up period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Qualification 
A qualification period of up to 2 weeks (unless approved by the Sponsor) is given to complete 
qualification assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and 
Appendix A. 


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3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for assessments at 
specified intervals throughout the 52-week treatment period as detailed in the Schedule of Procedures 
(Appendix A).  During the treatment period, volanesorsen is administered by SC injection once weekly. 
3.4.3 
Extended Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of continuing dosing for 
up to an additional 52 weeks.  Patients not continuing dosing will enter the 26-week post-treatment 
follow-up.   
3.4.4 
Post-Treatment Follow-Up 
The post-treatment follow-up period is at least 26 weeks and consists of at least 9 Study Center visits on 
Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 (Weeks 53, 54, 55, 56, 57, 58, and 71 may be conducted by a 
home healthcare nurse).  
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, tolerability 
and efficacy data collected on volanesorsen during this study.  Based on its ongoing assessment of the 
safety and tolerability of volanesorsen, the DSMB will provide recommendations to the Sponsor for 
modifying, stopping or continuing the study as planned.  Details on the safety assessments, frequency of 
review and meeting schedules are outlined in the DSMB Charter and/or the statistical analysis plan 
(SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s written 
independent ethics committee/institutional review board (IEC/IRB) approval of the protocol, informed 
consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-specific 
procedures or evaluations related to this open-label study are performed.   
During the qualification period, the eligibility of the patient to enroll in the open-label study will be 
determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may be used for 
qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or ISIS 304801-CS16 
index studies (unless approved by the Sponsor) is given to complete qualification.  Qualified patients will 
retain the unique patient identification number that was assigned to them during the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies.  The patient identification number will be used to identify the patient 
throughout the extension trial and must be used on all study documentation related to that patient.  The 
patient identification number must remain constant throughout the extension trial. 


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4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all qualification assessments have been 
completed and after the Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  
No patient may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria within 2 
weeks of Study Day 1, or at the time point specified in the individual eligibility criterion listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index 
studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the following criteria in 
order to enter into the open-label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a creamy 
top layer after ultracentrifugation of a fasting blood sample) or documentation of fasting TG 
measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
supported by documentation of at least 1 of the following: 
• 
Confirmed homozygote, compound heterozygote or double heterozygote for known loss-
of-function mutations in Type 1-causing genes (such as LPL, apoC-II, GPIHBP1, or 
LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical history.  Note: testing of 
LPL activity should not be performed to confirm eligibility for the study. 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 index study 
4. Able and willing to participate in a 78-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal (defined as 
12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 years, 
12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels 
in the postmenopausal range for the laboratory involved), abstinent*, or if engaged in sexual 
relations of child-bearing potential, patient is using an acceptable contraceptive method (refer 
to Section 6.3.1) from time of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration. 


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b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of child-
bearing potential, patient is utilizing an acceptable contraceptive method (refer to 
Section 6.3.1) from the time of signing the informed consent form until 13 weeks after the 
last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
5.2 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of Qualification 
b. HbA1c ≥ 9.0% at Qualification 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of Qualification [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of the 
Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to Qualification 
4. History within 6 months of Qualification of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack or 
unstable congestive cardiac failure requiring a change in medication or major surgery within 3 
months of Qualification 
5. Any of the following laboratory values at Qualification 
a. Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and documentation 
of Gilbert’s syndrome in which case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine dipstick.  In 
the event of a positive test eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on urine 
dipstick.  In the event of a positive test eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power field 


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• 
Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of Cockcroft-
Gault for estimation of GFR in patients with low body weight after discussion with 
Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Qualification 
d. LDL-C > 130 mg/dL at Qualification 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the Sponsor, 
would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding diathesis or 
coagulopathy or clinically-significant abnormality in coagulation parameters at Qualification 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed 
prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or 
chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma 
in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1 month of 
Qualification, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable dose for at 
least 3 months prior to Qualification and dose and regimen expected to remain constant 
during the treatment period.  Patients taking OTC omega-3 fatty acids should make every 
effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to Qualification 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Qualification unless 
approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable dose 
for at least 3 months prior to Qualification and dose and regimen expected to remain stable 
throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
Qualification and dose and regimen expected to remain constant during the treatment period 
f. 
Glybera gene therapy within 2 years prior to Qualification 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on a stable 
dose for at least 4 weeks prior to Qualification and regular clinical monitoring is performed 


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h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to 
Qualification and dose and regimen expected to remain constant during the treatment period 
i. 
Plasma apheresis within 4 weeks prior to Qualification or planned during the study 
j. 
Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to Qualification (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of > 499 mL within 60 days 
of Qualification 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or placebo) 
17. Have any other conditions, including new or worsening of existing condition, which, in the 
opinion of the Investigator or the Sponsor would make the patient unsuitable for inclusion, or 
could interfere with the patient participating in or completing the study 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification  
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through the last 
patient’s Week 13 visit of the open-label study or until results from the database locks for the ISIS 
304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 5 times 
during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be administered once 
weekly (Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant medication/procedure 
information, lipid panel, blood viscosity, volanesorsen plasma concentrations, immunogenicity (IM) 
testing, platelet aggregation, liver/spleen MRI, ECGs, echocardiograms and quality of life assessments 
will be performed according to the schedule of procedures in Appendix A.  Adverse events at the 
injection site should be collected as adverse events.  Dietary counseling will be reinforced at intervals 
throughout the treatment and follow-up period and all patients will complete a daily food diary for one 
week prior to their quarterly visit.  All blood and urine samples should be collected prior to volanesorsen 
administration.  Blood sampling at Weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 
23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51 
may be conducted by a home healthcare nurse.  Approval for study procedures to be conducted by a home 
healthcare nurse on other outpatient visit days will require prior approval by the Sponsor.  Patients must 
be fasted prior to drawing all blood samples and samples drawn locally should also be sent to the central 
laboratory for analysis whenever possible.  Dosing instructions and training will be provided to the 
patient where applicable. 


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All reasonable attempts should be made to ensure compliance with the visit schedule as outlined in 
Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent visits should 
be calculated based on the time elapsed since Day 1 rather than from the date of the previous visit. 
6.1.3 
Extended Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of continuing dosing for 
up to an additional 52 weeks. 
During the extended treatment period, patients will have assessments and procedures done during Weeks 
54-104 as per the Schedule of Procedures in Appendix A.  Assessments and procedures may be conducted 
by either a home healthcare service or the Study Center, however the patient will be required to visit the 
study center approximately every 3 months.  Study Drug will be administered once weekly unless the 
patient is on a biweekly dosing schedule for safety reasons (Section 8.1).  Collection and measurement of 
vital signs, clinical laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, IM 
testing, ECGs, and physical examinations will be performed according to the Schedule of Procedures in 
Appendix A.  Adverse events at the injection site should be collected as adverse events.  Dietary 
counseling will be reinforced at intervals throughout the extended treatment period.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 53, 54, 55, 
56, 57, 58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 
86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103 may be conducted by a home 
healthcare nurse.  Approval for study procedures to be conducted by a home healthcare nurse on other 
outpatient visit days will require prior approval by the Sponsor.  Patients must be fasted prior to drawing 
all blood samples and samples drawn locally should also be sent to the central laboratory for analysis 
whenever possible.  Dosing instructions and training will be provided to the patient where applicable. 
6.1.4 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup will have 
more frequent PK sampling over a 24-hour period following the first dose on Study Day 1 in order to 
evaluate the plasma PK parameters of volanesorsen.  Patients in this subgroup will have an additional 
visit to the clinic, or by a home healthcare nurse, on Day 2 to collect a 24-hour post-dose blood draw after 
dosing on Day 1.  The detailed PK sampling schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn for the 
subgroup-specific procedures (e.g., multiple blood draws for PK) without being withdrawn from the 
study.  If a patient withdraws consent from the subgroup procedures, he/she should remain on study and 
continue to follow all the non-subgroup assessments and procedures as outlined in Appendix A. 
6.1.5 
Post-Treatment Follow-up 
After completion of the Week 52 visit assessments, patients will have the option of continuing dosing for 
up to an additional 52 weeks as described in Section 6.1.3.  Patients not continuing dosing will enter the 
26-week post-treatment follow-up.  The 26-week post-treatment follow-up consists of at least 9 Study 
Center visits on Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 (Weeks 53, 54, 55, 56, 57, 58, and 71 may 
be conducted by a home healthcare nurse). An additional 26-week post-treatment follow-up occurs after 
the extended treatment period with at least 9 Study Center visits on Weeks 105, 106, 107, 108, 109, 110, 
117, 118, and 125 (Weeks 105, 106, 107, 108, 109, 110, and 118 may be conducted by a home healthcare 
nurse. These visits are outlined in the Schedule of Procedures in Appendix A. 


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6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is contained in 
Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample 
should be collected in parallel and analyzed locally.  In the event that both the central and local sample 
are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1 week and the result must be reviewed by the Investigator and confirmed to be acceptable before 
dosing can continue.  All platelet count results will be promptly reviewed by the Investigator to determine 
if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 
75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and body 
temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a sitting position 
for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should always be measured on 
the same arm (preferentially on the left arm).  Height will be measured at the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma since their 
last visit and the number/duration of the events will be recorded.  Physical exams should also include skin 
examination for presence/resolution of eruptive xanthomas.  If a patient experiences an episode of 
eruptive xanthoma during the study, photos of the area should be taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of the first 
dose of Study Drug (for ISIS 304801-CS16 roll over patients) and repeated at Week 52.  Images will be 
evaluated by an independent assessor, blinded to the patient’s treatment assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic valve 
function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of assessment of 
treatment-emergent changes, all echocardiograms will be evaluated on an ongoing basis by an 
independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 5 minutes.  
ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52. During the post-treatment 
follow-up, ECGs will be performed in triplicate at Weeks 65 and 78 for patients not opting to participate 
in the Extended Treatment Period.  Patients in the Extended Treatment Period will have ECGs performed 
in triplicate at Weeks 76, 104 and 130. 


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6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, Week 13, 
Week 26, and Week 52. During the post-treatment follow-up, patients will complete an EQ-5D and SF-36 
during Weeks 65 and 78. Additional Quality of Life Questionnaires will be collected at Weeks 117 and 
130 should the patient enter the extended treatment period post-treatment follow-up. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, Week 26, 
Week 52. During the post-treatment follow-up, patients will complete a 7-day food diary prior to 
Weeks 65 and 78. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient to 
provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, telephone 
calls from a dietitian or qualified study personnel to assess as to how each patient is maintaining 
their diet will be conducted randomly during the treatment and post treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior to 
screening and information relating to these events will be collected for independent adjudication.  
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and either 
be abstinent or, if engaged in sexual relations of child-bearing potential, practice effective contraception 
from the time of signing the informed consent form until at least 13 weeks after their last dose of study 
treatment. 


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Male patients must also encourage their female partner to use effective contraception from the time of 
signing the informed consent until 13 weeks after the subject’s last dose of study treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who has 
experienced menarche, and who does not meet 1 of the following conditions: 
•
Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, in
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical
cause and FSH levels in the postmenopausal range for the laboratory involved
•
6 weeks after surgical bilateral oophorectomy with or without hysterectomy
•
Post hysterectomy
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
•
Effective male contraception includes a vasectomy with negative semen analysis at follow-up, or 
the use of condoms together with spermicidal foam/gel/film/ cream/suppository.  Male patients 
must also encourage their female partner to use effective contraception from the time of signing 
the informed consent until 3 months after the patient’s last dose of study treatment.  Effective 
contraceptive for the female partner includes: surgical sterilization (e.g., bilateral tubal ligation), 
hormonal contraception, intrauterine contraception/device, or barrier methods (female condom*, 
diaphragm, sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository. 
Male patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug.
For female patients: 
•
Using 1 or more of the following acceptable methods of contraception:  surgical sterilization
(e.g., bilateral tubal ligation), hormonal contraception, intrauterine contraception/device, or any 2
barrier methods (a combination of male or female condom* with diaphragm, sponge, or cervical
cap) together with spermicidal foam/gel/film/cream/suppository.
* Note: A female condom and a male condom should not be used together as friction between the two can
result in either product failing. 
† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods 
of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours before 
visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial and that 


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serum lipase and/or amylase measures should be done in order to adjudicate the event, based on Atlanta 
Classification (Banks et al. 2013).  If serum or amylase activity is less than 3 x upper limit of normal 
(ULN), imaging, preferably contrast-enhanced computed tomography, should be considered to confirm 
the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its storage 
and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen must be stored 
securely at 2 °C to 8 °C and be protected from light. 
Table 1 Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of volanesorsen 
provided by the Sponsor.  The Study Center must return all unused volanesorsen to the Sponsor or 
designee.  All used syringes must be disposed of as per the site’s hazardous waste destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 300 mg 
injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on a reduced dose 
or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons in their index study 
(ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or dose frequency of volanesorsen 
for continued safety or tolerability as outlined in Sections 8.5 and 8.6.  Patients entering this CS7 study 
having dose or dose frequency reduced in the CS16 index study after 13 weeks of treatment, as outlined 
in CS16 Amendment 4 Section 8.7, can receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example, if a patient receives the first dose on a Monday, subsequent doses should be given on Mondays, 
if possible.  If a patient misses an injection, or if dosing on the usual day is not possible, the patient can 
reschedule the injection provided that 2 doses are administered at least 2 days apart. 


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Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose assessment and 
the last measurement prior to Day 1 (e.g., qualification assessments or assessments from the final visits of 
ISIS 304801-CS6 and ISIS 304801-CS16 index studies if used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are provided 
for the monitoring of selected parameters chosen based on preclinical and clinical observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), the initial 
clinical laboratory results meeting the safety monitoring or stopping criteria presented below must be 
confirmed by performing measurements (ideally in the same laboratory that performed the initial 
measurement) on new specimens.  All new specimen collections should take place as soon as possible 
(ideally within 3 days of the initial collection).  For stopping rules, if the initial laboratory result is 
observed during the Treatment Period, the results from the retest must be available prior to administering 
the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request confirmation of 
additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must not be re-
dosed until the re-test results are available.  In general, patients who do not meet the stopping rules based 
upon retest may continue dosing.  However, the Investigator and the Sponsor Medical Monitor (or 
appropriately qualified designee) should confer as to whether additional close monitoring of the patient is 
appropriate.  Reduction in dose or dose frequency may also be initiated as noted in Section 8.7.  If any of 
the stopping criteria described below (refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose 
paused or permanently discontinued (as described in the stopping criterion concerned) from further 
treatment with volanesorsen and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver Injury:  
Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human Services, Food 


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and Drug Administration, July 2009.  For a definition of Baseline please refer to guidance in Section 8.5 
above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline value or 3 x 
ULN if the baseline value was > ULN) at any time during the study (Treatment or Post-Treatment 
Period), the initial measurement(s) should be confirmed as described above.  Additional confirmatory 
measurements should also be performed if ALT or AST levels increase to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or the 
greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their liver 
chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio (INR) and total 
bilirubin) retested at least once-weekly until ALT and AST levels become ≤ 1.2 x ULN or 1.2 x baseline 
value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST levels > 
3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN), the following 
evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV antibody 
panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or MRI 
scans, may be performed at the discretion of the Investigator, in consultation with the Sponsor Medical 
Monitor.  Repetition of the above evaluations should be considered if a patient’s ALT and/or AST levels 
reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3. 
Monitor every 1 week unless otherwise specified. 
Study Drug administration is contingent on the availability of the immediately preceding test result.  An 
interpretable platelet value must be available within 7 days prior to dosing.  Only the study doctor or 
qualified designee can authorize continued Study Drug administration based on an acceptable platelet 
value.  Patients should not administer a dose until they have been contacted by their study doctor or 
designee and told that it is acceptable to dose.  Authorization to dose must be documented in the patient’s 
medical records. 
Due to the 1 to 2-year study duration it is anticipated that patients may undertake travel including 
vacations, which may impede weekly platelet monitoring.  In some situations, it may be possible to 
arrange for local laboratory testing or use of the home healthcare service at their temporary location.  The 
intent is to maintain weekly platelet monitoring and dosing where possible, as well as Investigator site 
contact with the study patients.  However, if the above options are not possible, a temporary interruption 


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of study treatment will be planned with a prompt blood draw upon the patient’s return which must be 
reported and reviewed by the Investigator prior to the patient resuming dosing. 
The tests outlined in Table 2 should also be performed as soon as possible.  Additional lab tests will be 
determined by the Sponsor Medical Monitor or designee in consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor (See 
also Stopping Rules Section 8.6.3). 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower Limit of 
Normal (x2) or < 100,000/mm3 (x1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) of platelet count less than the 
lower limit of normal or who have any 1 occurrence of platelets < 100,000/mm3.  Labs only need to be 
performed once.  Labs may be collected over multiple visits, if blood requirements are a concern, as per 
investigator discretion. 
Note: 
The following labs may change as additional data is assessed, and sites will be updated regarding 
any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 


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8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-relevant, 
non-major bleeding events (which are defined in Section 8.6.3), for example excess bruising, petechiae, 
gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the Investigator must notify the 
Sponsor Medical Monitor and additional testing of coagulation parameters activated partial 
thromboplastin time (aPTT), prothrombin time (PT), INR and platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional symptoms 
that may arise during the study and the Investigator should closely evaluate all potential causes, including 
concomitant illness.  Patients that experience persistent constitutional symptoms should be discussed with 
the Sponsor Medical Monitor or designee to determine whether additional monitoring or laboratory tests 
are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has a low-
density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with T2DM) on 2 
consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded for the remainder of the 
study and the Investigator will be encouraged to initiate/adjust treatment to lower LDL-C according to 
country-specific guidelines (e.g., initiate statin therapy or increase the statin dose for patients who are 
already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard practice 
guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In addition, patients 
who are not on insulin but use a glucometer should also bring their glucometer and/or glucometer log 
printout to every clinic visit. 
• 
The Investigator or delegate will review the glucometer reading or printout at every clinic visit to 
evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed threshold values as 
per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, as well 
as any hypoglycemic episode they may experience. 
• 
The Investigator or delegate will ask patients at every clinic visit if they made changes in their 
insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic episodes at 
each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse events in the 
adverse event CRF. Documented symptomatic hypoglycemia is defined as typical 
hypoglycemia symptoms accompanied by measured plasma glucose ≤ 70 mg/dL (≤ 3.9 
mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 


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8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as one in which the patient requires assistance of 
another person to obtain treatment for the event and has a plasma glucose level ≤ 70 mg/dL (≤ 3.9 
mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or buccal or intramuscular 
glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place patients at 
risk for injury to themselves or others.  Note that “requires assistance” means that the patient could not 
help himself or herself.  Someone being kind that assists spontaneously the patient when not necessary 
does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take immediate action 
to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are certain 
classical signs and symptoms, of which patients should be aware as a clue that their blood glucose may be 
low.  Common symptoms include headache, heart pounding, confusion, disorientation, numbness or 
tingling, pale skin, shakiness or tremulousness, increased appetite, anxiousness or nervousness, 
lightheadedness or dizziness, sweating, and weakness.  Coma could occur if blood sugar correction is not 
performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood glucose 
using their meters as soon as possible, before treatment if possible, provided they feel it is safe to do so.  
If there is doubt about safety they should treat the event first, using some sugar, milk, or juice for 
example, then obtain and record a blood glucose value as soon as possible thereafter.  The time and nature 
of treatment should be noted, and especially if any blood glucose result was before or after treatment.  It 
would be helpful for the patient to note if a contributory factor (e.g., missed or reduced meals, 
unaccustomed physical activity) occurred earlier in the day of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be allowed during 
the course of the study, unless specific threshold values are met at Week 13 or later and confirmed on 
subsequent testing (ideally within 1 week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should self-
monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  If a fasting 
pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should check it again on the 
following 2 days.  If all the fasting pre-breakfast values on 3 consecutive days exceed the specific limit, 
the patient should contact the Investigator and an unscheduled central laboratory FPG measurement and 
HbA1c should be performed. 
The threshold values are defined as: 
• 
FPG > 270 mg/dL (15.0 mmol/L) 
• 
HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 1% from 
baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 


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In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that no 
reasonable explanation exists for insufficient glucose control and in particular that: 
• 
Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours fast) 
• 
Absence of intercurrent disease which may jeopardize glycemic control.  In case of an emergency 
(e.g., surgery, infection), the Investigator can take appropriate measures for glycemic control 
• 
Compliance to treatment is appropriate 
• 
Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator should 
consider the following: 
• 
Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• 
Stress on the absolute need to be compliant to treatment 
• 
Organize a specific interview with a Registered Dietician or other qualified nutrition professional 
and stress on the absolute need to be compliant to diet and lifestyle recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  If none 
from the above-mentioned reasons can be found, or if appropriate action fails to decrease FPG/HbA1c 
under the threshold values, additional medication may be introduced at the Investigator’s discretion and 
according to local guidelines after discussion with the Sponsor Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended temporarily 
until the patient is clinically stable.  The suitability of the patient for continued dosing and the need for 
any modification to treatment schedule (refer to Section 8.7) will be determined by the Investigator in 
consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose assessment and the 
last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an alternative 
explanation as discussed with the Sponsor Medical Monitor, dosing of a patient with volanesorsen 
will be stopped permanently; values that are not confirmed due to failure to retest or missing lab values 
will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 


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4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), which is confirmed, and the new appearance (i.e., onset coincides with the changes in 
hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, or eosinophilia (> ULN) felt by the Investigator to be potentially related to hepatic 
inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 3 criteria 
below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL (26.5 μmol/L) and 
≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault ≤ 40 
mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these criteria will 
be determined by the Investigator in consultation with the Sponsor Medical Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or clinically-
relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient with volanesorsen 
will be stopped permanently.  The follow-up schedule for any events meeting this stopping criterion will 
be determined by the Investigator in consultation with the Sponsor Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a rate of decline ≥ 50% between two 
consecutive assessments, irrespective of the platelet level, or a platelet count less than 75,000/mm3 that 
occurs while the patient is on dosing at 300 mg every 2 weeks, then dosing of a patient with volanesorsen 
will be stopped permanently.  Platelet count will be monitored as outlined in Table 3. 
Administration of steroids is recommended for patients whose platelet count is less than 50,000/mm3.  
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment 
guidelines for immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily 
for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or 
Methylprednisolone 30 mg/kg/day for 7 days  
(note:  may require continuation with oral steroids after methylprednisolone).  In order to reduce the 
unlikely but potential increased risk of pancreatitis during the period of corticosteroid therapy, 
triglyceride levels will be monitored weekly, and AE monitoring will continue, during corticosteroid 
treatment and the laboratory alert will be changed from an increase of 2,000 to 500 mg/dL during that 
period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or clinically-
relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient with volanesorsen 
should be suspended temporarily until the platelet count has recovered to> 100,000/mm3.  If dosing is 
continued it should be at a reduced dose frequency of 300 mg every 2 weeks (refer to Section 8.7).  The 


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suitability of the patient for continued dosing will be determined by the Investigator in consultation with 
the Study Medical Monitor and will be based on factors such as the original rate of decline in the patient’s 
platelet count, whether any bleeding events were experienced by the patient, and the speed of recovery of 
platelet count upon holding of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing of the 
patient with Study Drug will be stopped permanently. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• 
Fatal bleeding, and/or 
• 
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
retroperitoneal, intraarterial or pericardial, or intramuscular with compartment syndrome, and/or 
• 
Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 24 hours, or 
leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
 
Study Drug administration is contingent on the 
availability of the immediately preceding test 
result.  An interpretable platelet value must be 
available within 7 days prior to dosing.  Only 
the study doctor or qualified designee can 
authorize continued Study Drug administration 
based on an acceptable platelet value.  Patients 
should not administer a dose until they have 
been contacted by their study doctor or 
designee and told that it is acceptable to dose.  
Authorization to dose must be documented in 
the patient’s medical records. 
Monitor every 1 week unless 
otherwise specified 
Obtain additional lab tests  
(Table 2) if 2 occurrences consecutive 
or non-consecutive of platelet count 
140K - > 100K/mm3 or 1 occurrence 
of platelet count ≤ 100K/mm3.  Labs 
only need to be performed once.  Labs 
may be collected over multiple visits, 
if blood requirements are a concern, as 
per Investigator discretion. 
> 100K/mm3 
Weekly 300 mg Study Drug administration 
 
100K/mm3 - >75K/mm3 
Permanently reduce dose frequency to 300 mg 
every 2 weeks  


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Platelet Count on Rx 
Drug Dose 
Monitoring 
75K/mm3 - >50K/mm3 
• 
If occurs while on dose of 300 mg every 
2 weeks then permanently discontinue 
Study Drug, otherwise dose pause. 
• 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks only 
if approved by Sponsor Medical 
Monitor 
• 
Monitor every 2-3 days until 
2 successive values are 
> 75K/mm3 then monitor every 1 
week 
• 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
< 50K/mm3 or a rate of decline ≥ 
50% between two consecutive 
assessments, irrespective of the 
platelet level 
Permanently discontinue Study Drug   
• Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
2 successive values are > 75K/mm3 
then monitor every 1 week 
• Patient should be evaluated by a 
hematologist to provide diagnostic 
and therapeutic management 
• Steroids recommended *.  It is 
strongly recommended that, unless 
the patient has a medical 
contraindication to receiving 
glucocorticoids, the patient receives 
glucocorticoid therapy to reverse the 
platelet decline.   
• Monitor triglyceride levels weekly 
and continue AE monitoring during 
steroid therapy  
• Discontinue antiplatelet agents/ 
NSAIDS/ anticoagulant medication 
while platelet count is< 50K/mm3 if 
possible 
Legend: 
* 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; 
Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days (note:  may require 
continuation with oral steroids after Methylprednisolone).  In order to reduce the unlikely but potential increased risk of 
pancreatitis during the period of corticosteroid therapy, triglyceride levels will be monitored weekly, and AE monitoring 
will continue, during corticosteroid treatment and the laboratory alert will be changed from an increase of 2,000 to 500 
mg/dL during that period. 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and Table 3 
(above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose frequency will 
be allowed for safety and tolerability.  Any proposed adjustment to treatment schedule must be discussed 
with, and approved by, the Study Medical Monitor prior to initiation.  Up to 2 adjustments in the 
treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 


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8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• 
The patient becomes pregnant.  Report the pregnancy according to instructions in Section 9.5.4 
• 
The patient withdraws consent 
• 
The patient experiences an AE that necessitates permanent discontinuation of study treatment 
• 
The patient develops laboratory test abnormalities that meet any of the stopping rules listed in 
Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the platelet 
monitoring rules shown in Table 3 in Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  
Following this period, if the platelet count is stable (at least 3 consecutive values that are stable as 
determined by the Sponsor Medical Monitor and > 100,000/mm3), the next platelet count should be taken 
within at least 6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study 
Drug.  Patients should also be strongly encouraged to attend applicable landmark visits at Weeks 12, 13, 
25, 26, and 50, 52 (calculated based on the time elapsed since Day 1) to collect fasting lipid panels and 
conduct safety assessments in accordance with the Schedule of Procedures in Appendix A.  Any patient 
who discontinues treatment after Week 44 should also be strongly encouraged to attend a final follow-up 
visit (Week 78 visit assessments) approximately 26 weeks after their last dose of Study Drug, in addition 
to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and ideally 
within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up Period should 
be encouraged to follow the platelet monitoring rules shown in Table 3 in Section 8.6.3 for the first 6 
weeks after discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 3 
consecutive values that are stable as determined by the Sponsor Medical Monitor and > 100,000/mm3), 
the next platelet count should be taken within at least 6 weeks so that patients are monitored for at least 12 
weeks after discontinuing Study Drug.  Patients should also be encouraged to undergo a final follow-up 
visit (Week 78, see Appendix A) prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange for the 
patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• 
Withdrawal of consent 
• 
The patient is unwilling or unable to comply with the protocol 


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Other reasons for withdrawal of patients from the study might include: 
• 
At the discretion of the Investigator for medical reasons 
• 
At the discretion of the Investigator or Sponsor for noncompliance 
• 
Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to the date 
of withdrawal.  All information, including the reason for withdrawal from study, must be recorded in the 
CRF. 
Any patient who withdraws consent to participate in the study will be removed from further treatment and 
study observation immediately upon the date of request.  These patients should be encouraged to 
complete the ET study procedures and observations at the time of withdrawal (see Section 8.8 and 
Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made to 
complete the early termination study procedures and observations at the time of withdrawal (see 
Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s CRF.  
AEs related to administration of these therapies or procedures must also be documented on the 
appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-counter 
medications, herbal medications and vitamin supplements) administered between signing informed 
consent and completion of the post-treatment follow-up period.  All concomitant medications/treatments 
and significant non-drug therapies (including supplements and assistive devices) received by a patient, 
including changes in the patient’s current medications, must be recorded in the patient’s source 
documents and CRF.  Patients taking over the counter (OTC) omega-3 fatty acids should make every 
effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the disallowed 
concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 fatty acids 
[including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, or systemic 
corticosteroids may be started or adjusted after baseline Qualification.  Doses of existing oral anti-diabetic 
medication, oral contraceptives, hormone replacement therapy, anticoagulants, or drugs or dietary 
supplements with potential lipid-altering effects should not be adjusted.  Study patients are prohibited 
from receiving other experimental agents during the study.  This includes marketed agents at 
experimental dosages that are being tested for the treatment of hypertriglyceridemia. 


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Patients should consult with the Site Investigator or designee prior to initiating any new medication, 
including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) or 
diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between signing of 
informed consent and Week 78 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The Study 
Center staff is required to document the receipt, dispensing, and return/destruction of volanesorsen.  
Patients that are self-administering volanesorsen at home must record treatment in a dosing diary that will 
be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with the 
Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of serious 
adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs) per the 
International Conference on Harmonization (ICH) guidelines E2A and ICH E6 (R2).  Country-specific 
regulatory requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any SAE 
according to applicable regulations.  The Independent DSMB will be notified of any SAE as specified in 
the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate the 
available information and perform an independent assessment of relatedness.  While the Sponsor may 
upgrade an Investigator’s decision it is not permissible to downgrade the Investigator’s opinion for the 
purposes of determining whether the SAE meets the definition of a SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an individual basis 
in an expedited manner because they are anticipated to occur in the study population independent of 
volanesorsen exposure.  The Investigator still has the responsibility to report all SAEs to the Sponsor as 
described in Sections 9.4.1 to 9.4.3.5. 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and the 
Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis acute, 
pancreatitis chronic, pancreatitis necrotizing, pancreatitis 
relapsing 
0.2-0.35 events per patient-year  
 


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Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The Sponsor and 
DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate of the event compared 
to the rate expected in a non-volanesorsen exposed population.  If the aggregate analysis indicates that an 
event is occurring significantly more frequently or at a greater severity than expected, then the event will 
be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether there is a 
reasonable possibility that the drug caused the event.  If the event is considered by the Sponsor or 
designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the study or use of 
investigational drug product, whether or not the AE is considered related to the investigational drug 
product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or Sponsor, meets 
any of the following criteria: 
• 
Results in death 
• 
Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not include 
an AE or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Hospitalization is defined as an admission of greater than 24 hours to a medical facility and does 
not always qualify as an AE 
• 
Results in a persistent or significant incapacity or substantial disruption of the ability to conduct 
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• 
Results in congenital anomaly or birth defect in the offspring of the patient (whether the patient is 
male or female) 
• 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may also be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the study 
(i.e., before informed consent) should be recorded as Medical History and not recorded as AEs unless the 
pre-existing condition worsened.  The Investigator should always group signs and symptoms into a single 
term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to volanesorsen) should be reported to the Sponsor or designee within 24 hours of the 
Study Center’s first knowledge of the event.  The collection of SAEs will begin after the patient signs the 
informed consent form and stop at the end of the patient’s follow-up period which is defined as the Week 
78 visit.  When the Investigator is reporting by telephone, it is important to speak to someone in person 
versus leaving a message.  An Initial Serious Adverse Event Form should be completed and a copy 
should be faxed to the Sponsor or designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse Event Forms 
as soon as additional information becomes available.  All SAEs will be followed until resolution.  SAEs 
that remain ongoing past the patient’s last protocol-specified follow-up visit will be evaluated by the 
Investigator and Sponsor.  If the Investigator and Sponsor agree the patient’s condition is unlikely to 
resolve, the Investigator and Sponsor will determine the follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form and will 
stop at the end of the patient’s follow-up period, which is defined as the Week 78 visit.  The Investigator 
will monitor each patient closely and record all observed or volunteered AEs on the Adverse Event Case 
Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case Report 
Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• 
Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
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• 
Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event and 
volanesorsen administration 
• 
Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is unlikely (For 
reporting purposes, Unlikely/Remote will be grouped together with Not Related) 
• 
Not Related:  The event can be readily explained by the patient’s underlying medical condition, 
concomitant therapy, or other causes, and therefore, the Investigator believes no relationship 
exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE not listed in 
Appendix D will be graded as follows: 
• 
Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual daily 
activities 
• 
Moderate:  The event causes the patient more discomfort and interrupts the patient’s usual daily 
activities 
• 
Severe:  The event is incapacitating and causes considerable interference with the patient’s usual 
daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• 
None:  No changes were made to volanesorsen administration and dose 
• 
Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• 
Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted or 
delayed due to the AE and restarted at the same dose 
• 
Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the Adverse 
Event Case Report Form (treatment should also be recorded on the concomitant treatment or ancillary 
procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• 
AE Persists:  Patient terminates from the trial and the AE continues 


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• 
Recovered:  Patient recovered completely from the AE 
• 
Became Serious:  The event became serious (the date that the event became serious should be 
recorded as the Resolution Date of that AE and the Onset Date of the corresponding SAE) 
• 
Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• 
Ongoing:  SAE continuing 
• 
Persists (as non-serious AE):  Patient has not fully recovered but the event no longer meets 
serious criteria and should be captured as an AE on the non-serious AE eCRF (the SAE resolution 
date should be entered as the date of onset of that AE) 
• 
Recovered:  Patient recovered completely from the SAE (the date of recovery should be entered 
as the SAE resolution date) 
• 
Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event (MACE) 
will be adjudicated by a blinded, independent committee as outlined in the MACE Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute pancreatitis will 
be adjudicated by a blinded, independent committee according to the Atlanta classification of acute 
pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis Adjudication Charter.  In addition, data 
for prior episodes of acute pancreatitis or suspected pancreatitis will be collected by review of each 
patient’s medical chart and these events will also be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, constitute or 
be associated with an AE.  Examples of these include abnormal laboratory results that are associated with 
symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, tetany due to hypocalcemia, or 
cardiac arrhythmias due to hyperkalemia.  Whenever possible, the underlying diagnosis should be listed 
in preference to abnormal laboratory values as AEs.  Clinically-significant abnormalities will be 
monitored by the Investigator until the parameter returns to its baseline value or until agreement is 
reached between the Investigator and Sponsor Medical Monitor.  Laboratory abnormalities deemed not 
clinically-significant (NCS) by the Investigator should not be reported as AEs.  Similarly, laboratory 
abnormalities reported as AEs by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed clinical 
laboratory reports will serve as source documents and should include the Investigator’s assessment of 
clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered an SAE, 
even if the patient is hospitalized; the Study Center must document all of the following: 


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• 
The prescheduled or elective procedure or routinely scheduled treatment was scheduled (or was 
on a waiting list to be scheduled) prior to obtaining the patient’s consent to participate in the 
study 
• 
The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the Investigator 
between the patient’s consent to participate in the study and the timing of the procedure or 
treatment 
• 
The prescheduled or elective procedure or routinely scheduled treatment is the sole reason for the 
intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description should be 
provided in the deviation, including whether the patient was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose of 
volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the symptom(s) 
should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to Investigator’s 
section of the Investigator’s Brochure and contact the Sponsor or designee within 24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate contraception 
with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes that he 
has made someone pregnant during the study, then the Study Center staff must be informed immediately.  
An Initial Pregnancy Form should be submitted to the Sponsor or designee within 24 hours of first 
learning of the occurrence of pregnancy.  Follow-up information including delivery or termination is 
reported on Follow-up Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a pregnancy 
test will be performed.  The patient with a confirmed pregnancy will be immediately withdrawn from 
treatment with volanesorsen.  However, the patient will be encouraged to complete the post-treatment 
follow-up portion of the study to the extent that study procedures do not interfere with the pregnancy.  
Regardless of continued study participation, the study physician will assist the patient in getting 
obstetrical care and the progress of the pregnancy will be followed until the outcome of the pregnancy is 
known (i.e., delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the birth 
of a child, the Study Center and Sponsor may require access to the mother and infant’s medical records 
for an additional 8 weeks after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed until the 
outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous abortion).  If the 
pregnancy results in the birth of a child, the Study Center and Sponsor may request access to the 


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mother and infant’s medical records for an additional 8 weeks after birth.  Follow-up will be 
performed to the extent permitted by applicable regulations and privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the average of 
Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 analysis time point 
is at the end of Month 6 are defined as the average of Week 25 (Day 169) and Week 26 (Day 176) fasting 
assessments, and the values at the Month 12 analysis time point are defined as the average of Week 50 
(Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during the treatment period 
• 
Percent change and change from baseline in other fasting lipid measurements including total 
cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• 
Adverse events including adjudicated events of pancreatitis and MACE 
• 
Vital signs and weight 
• 
Physical examinations  
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 


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10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active Study Drug 
and have a baseline TG assessment.  The FAS represents the practically-feasible intent-to-treat (ITT) 
population as delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of volanesorsen 
and with no significant protocol deviations that would be expected to affect efficacy and PD assessments.  
The detailed criteria will be specified and finalized prior to the final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have at least 1 
post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  Group 1 (ISIS 
304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the baseline in this open-label 
study, which is defined as the average of Day 1 pre-dose assessment and the last measurement prior to 
Day 1 (e.g., qualification assessments or assessments from final visit of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or ISIS 
304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study baseline.  For 
patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, baseline will be the last 
non-missing assessment prior to the first dose of Study Drug.  Details will be provided in the SAP. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label study or 
after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are locked and unblinded.  
Both safety and efficacy information from this open-label study may be summarized during this interim 
analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be provided in the 
patient data listings.  Patient data listings will be presented for all patients enrolled into the study.  
Descriptive summary statistics including n, mean, median, standard deviation, standard error, interquartile 
range (25th percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and 
counts and percentages for categorical variables will be used to summarize most data by treatment group 
of the index studies for patients on active Study Drug in the ISIS 304801-CS6 or ISIS 304801-CS16 
index studies, and pooled treatment naïve group which includes patients on placebo in index studies.  
Where appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided tests 
with 5% Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will be 
assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK endpoints will be 
assessed in the PK Set as applicable. 


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10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by treatment 
group and overall.  The patient disposition will be summarized by treatment group and overall.  All 
patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group and 
overall. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA preferred 
term, and treatment group of the index studies.  Narratives of treatment-emergent deaths, serious and 
significant AEs, including early withdrawals due to AEs, will also be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all treatment-
emergent serious AEs, and all treatment-emergent serious AEs potentially related to Study Drug will be 
summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term and 
severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) with 
differential, coagulation panel, IM, complement etc., will be summarized by study visits by treatment 
group. 
These safety variables will also be presented as change and percent change from baseline over time after 
Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will be 
summarized by treatment group.  Response rate of patients with fasting plasma TG < 750 mg/dL or 
achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and Month 12 will be 
summarized.  Response analysis will also be conducted using a range of fasting plasma TG thresholds for 
determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be summarized 
by treatment group for other fasting lipid measures including non-HDL-C, apoB, HDL-C, apoA-1, 
VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association between 
changes in lipid parameters and total amount of drug received will be examined, as appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event rate, 
quality of life assessments, and comparison of other symptoms including eruptive xanthomas and lipemia 
retinalis will be summarized by treatment group. 
Additional details of the analyses to be conducted will be provided in the SAP. 


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10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be summarized 
using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be carried out 
on each individual patient data set using data collected in the open-label study from the intensive PK 
subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., steady-state PK), 
depending on their earlier treatment in the index studies (Group 1 and 2 patients).  On Week 1 Day 1 of 
the open-label study, patients who received placebo in the index study will receive the first treatment of 
volanesorsen (single-dose PK), while patients who received volanesorsen in the index studies had been on 
volanesorsen treatment for 12 months (ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK 
data collected from these patients reflect steady-state PK.  The maximum observed drug concentration 
(Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  
Area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration (CL0-24h 
/F) will be calculated from CL0-24h /F = Actual Dose/AUC0-24h.  Mean residence time (MRT) from time 
zero to 24 hours after the SC administration will be calculated from the equation, MRT0-24h = AUMC0-24h 
/AUC0-24h, where AUMC0-24h is the area under the moment plasma concentration-time curve from time 
zero to 24 hours after the SC administration.  Other PK parameters, as appropriate, may be determined or 
calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM status.  
Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and results will 
be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not evaluable, and 
when applicable, titer of anti-volanesorsen antibodies) before, during, and after treatment with Study 
Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be listed by their prior treatment 
in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subject ADA status 
(positive/negative or not evaluable) for all evaluable patients, along with the study day associated with the 
first positive IM status emerged (Tfirst, i.e., onset of ADA development), the last positive IM status 
observed (Tlast), the last ADA sample collection day, and subject - peak titer if applicable, will be listed by 
their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  
Subjects with positive anti-volanesorsen antibody status may be further classified (when applicable) as 
being either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, positive, and 
unknown status by treatment group.  Furthermore, onset and titer of the ADA response, if applicable, will 
be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 


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Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy (e.g., 
%change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK (e.g., Ctrough) 
measures will be evaluated using graphical analysis and statistical analysis.  These analyses will be either 
conducted and included in the study report, or data pooled and analyzed from all available Phase 2 and 3 
studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential patient 
population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written informed 
consent from the patient after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study and before any protocol-specific qualification procedures or any Study 
Drug are administered.  The patient must be given sufficient time to consider whether to participate in the 
study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her primary care 
physician should be documented in the patient’s medical records and the informed consent form should 
be signed and personally dated by the patient and by the person who conducted the informed consent 
discussion (not necessarily an Investigator).  The original signed informed consent form should be 
retained in the Study Master File and in any other locations required by institutional policy, and a copy of 
the signed consent form should be provided to the patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 2002 
the applicable regulations and guidelines of current Good Clinical Practice (GCP) as well as the demands 
of national drug and data protection laws and other applicable regulatory requirements will be strictly 
followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and any 
proposed advertising material must be submitted to the IEC/IRB for written approval.  A copy of the 
written approval of the protocol and informed consent form must be received by the Sponsor before 
recruitment of patients into the study and shipment of volanesorsen.  A copy of the written approval of 
any other items/materials that must be approved by the Study Center or IEC/IRB must also be received by 
the Sponsor before recruitment of patients into the study and shipment of Study Drug.  The Investigator’s 
Brochure must be submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The Investigator 
should notify the IEC/IRB of deviations from the protocol in accordance with ICH GCP Section 4.5.2.  
The Investigator should also notify the IEC/IRB of serious adverse events occurring at the Study Center 
and other adverse event reports received from the Sponsor, in accordance with local procedures. 


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The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout the 
duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the IEC/IRB 
continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report forms 
(CRF) or other documents submitted to the Sponsor, patients should be identified by unique initials and a 
patient study number only.  Documents that are not for submission to the Sponsor (e.g., signed informed 
consent forms) should be kept in strict confidence by the Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the company, of the regulatory agency(s), and the 
IEC/IRB direct access to review the patient’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and reproducing any 
records and reports that are important to the evaluation of the study.  The Investigator is obligated to 
inform and obtain the consent of the patient to permit named representatives to have access to his/her 
study-related records without violating the confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement from the 
Investigator must be obtained for all protocol amendments and amendments to the informed consent 
document.  The regulatory authority and IEC/IRB must be informed of all amendments and give approval 
for any amendments likely to affect the safety of the patients or the conduct of the trial.  The Investigator 
must send a copy of the approval letter from the IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  The 
Investigator reserves the right to terminate their participation in the study, according to the terms of the 
site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the trial’s completion or 
early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application will be 
used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has delegated trial 
duties are recorded on a Sponsor-approved Delegation of Site Responsibilities Form. 
Source documents are original documents, data, and records from which the patient’s CRF data are 
obtained.  These include but are not limited to hospital records, clinical and office charts, laboratory and 
pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs may not be used as source 
documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and centralized 
filing system of all study-related (essential) documentation in accordance with Section 8 of the ICH 


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Guidelines E6 (R2), suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities.  Elements should include: 
• 
Patient files containing completed CRFs, informed consents, and supporting copies of source 
documentation 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, copies of pre-
study documentation and all correspondence to and from the IEC/IRB and the Sponsor 
• 
If volanesorsen supplies are maintained at the Study Center, proof of receipt, volanesorsen 
Accountability Record, Return of volanesorsen for Destruction, final study volanesorsen 
reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and be 
readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or and the 
Investigator.  Should the Investigator wish to assign the study records to another party or move them to 
another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and visiting 
the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the various 
records of the trial (e.g., CRFs and other pertinent data) provided that patient confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to 
local regulations on the conduct of clinical research.  The monitor should have access to patient medical 
records and other study-related records needed to verify the entries on the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit by 
representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of Study Center 
facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-related records will occur 
to evaluate the trial conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on patient data 
received by the Sponsor.  During this review, patient data will be checked for consistency, omissions, and 
any apparent discrepancies.  In addition, the data will be reviewed for adherence to the protocol and GCP.  
To resolve any questions arising from the clinical data management review process, data queries and/or 
Study Center notifications will be sent to the Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures will 
indicate that the principal Investigator inspected or reviewed the data on the CRF, the data queries, and 
the Study Center notifications, and agrees with the content. 


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12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications should be 
recorded in English if possible, unless it is a combination drug, then record the trade name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow applicable local 
compensation laws.  Patients will be treated and/or compensated for any study-related illness/injury in 
accordance with the information provided in the Compensation for Injury section of the Informed Consent 
document.


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13. 
REFERENCES 
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to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 


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Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 
Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 


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Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692.


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14. 
APPENDICES 
 
 
 
Appendix A 
Schedule of Procedures 
 
Qualification through Treatment Period 
Post-Treatment Follow-up 
Extended Treatment Period 
Extended Treatment Period Post-Treatment Follow-Up 
 


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Appendix A 
Schedule of Procedures – Qualification through Treatment Period 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
Xj 
Xj 
X
j 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight (+ height on Day 1 only) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
Xk 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
CBC with Differentialb 
X 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
Serum Lipid Panel 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Blood viscosityr 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Platelet aggregationr 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Coagulation (aPTT, PT, INR) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
Xn 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Plasma PK - Volanesorsen 
 
Xl 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
FSH (women only, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Archived Serum & Plasma Samplese 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Troponin Io 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Bound Autoantibodiesr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archive blood sample for potential gene sequencing 
related to hypertriglyceridemia (Group 2 if not available 
from index study)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A 
Schedule of Procedures - Qualification through Treatment Period Continued 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to -1 
Wk 
1 
W
k 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to 
 -7 
1 
2 
22 
36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Urinalysisc 
X 
Xm 
 
X 
 
X 
 
 
Xm 
 
Xm 
 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Genetic testing for FCS diagnosis (if not 
available in medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Food/Drink Diary (quarterly)h 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Diet/Alcohol Counselingi 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Appendix A 
Schedule of Procedures – Post-Treatment Follow-up  
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 
540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Outpatient Visit 
Xj 
Xj 
X 
Xj 
X 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
Blood Draw (Fasting)c 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialb 
Xs 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
Serum Pregnancy Testd 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplese 
 
 
X 
 
X 
Urinalysisc 
 
Xm 
Xm 
Xm 
Xm 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Legend: 
a 
Qualification procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in 
parallel and analyzed locally.  In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or 
clumped blood samples) another sample must be repeated within 1 week and the result must be reviewed by the Investigator and 
confirmed to be acceptable before dosing can continue.  All platelet count results will be promptly reviewed by the Investigator 
to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 
75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During 
treatment period urine and blood samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK 
blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events 
(e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of kidney function, measurement of 
antibodies, etc.) in this or subsequent clinical studies of volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 ISIS 
304801-CS16 roll over patients) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
g 
Genetic testing can be conducted for study Qualification (Group 2 ISIS 304801-CS16 roll over patients); genetic testing will only 
be conducted if allowed in the geographic region and only after the patient has given specific written informed consent for 
genetic testing 


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h 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be 
performed by dietician or study personnel 
j 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study 
Center personnel 
k 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
l 
Full or abbreviated PK profile (see Appendix C) 
m 
Expanded urinalysis (see Appendix B) 
n 
HbA1c only 
o 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
p 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until apoC-III levels 
return to baseline values 
q 
Patient charts will be reviewed in order to collect data for events of acute pancreatitis or suspected pancreatitis in the patient’s 
medical history.  Chart review may be conducted at any time during the study.  These events will be adjudicated in the same 
manner as for events of pancreatitis during the study 
r 
May be done.  Blood viscosity and platelet aggregation in volanesorsen-treatment naïve patients only 
s 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling


ISIS 304801-CS7 
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25 May 2018 
 
73 
Appendix A 
Schedule of Procedures – Extended Treatment Period 
Study Period 
Extended Treatment Period 
Study Week 
Wk 54 
& 56 
Wk 
58 
Wk 60 
& 62 
Mo 15 
Wk 64 
Wk 66 
& 68 
Wk 
70 
Wk 72 
& 74 
Mo 18 
Wk 76 
Wk 78 
& 80 
Wk 
82 
Wk 84, 86, 
& 88 
Mo 21 
Wk 90 
Wk 92 
& 94 
Wk 
96 
Wk 98, 
100 & 
102 
Mo 24 
Wk 104 
Study Day 
372 & 
386 
400 
414 & 
428  
442 
456 & 
470 
484 
498 & 
512 
526 
540 & 
554 
568  582, 596 & 
610 
624 
638 & 
652 
666 680, 694 
& 708 
722 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Outpatient Visit 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Vital Signs (+ body weight) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urinalysis (including P/C ratio) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood Draw (Fasting)b 
Chemistry Panel 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC with Differentiala 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
Serum Lipid Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Troponin I 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Plasma PK - ISIS 304801c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Anti-ISIS 304801 Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum Pregnancy Testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Weekly Study Drug: SC Injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet/Alcohol Counselinge 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Legend: 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. In the event that 
both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 1 week and the result must be 
reviewed by the Investigator and confirmed to be acceptable before dosing can continue.  All platelet count results will be promptly reviewed by the Investigator to determine 


ISIS 304801-CS7 
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25 May 2018 
 
74 
if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be 
reported in an expedited fashion to the Sponsor 
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood samples will be 
collected prior to Study Drug administration 
c 
Abbreviated PK collection (see Appendix C) 
d 
Females of childbearing potential only 
e 
To reinforce compliance to the diet and alcohol restrictions 
f 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 


ISIS 304801-CS7 
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Protocol - France 
25 May 2018 
 
75 
 
Appendix A 
Schedule of Procedures – Extended Treatment Period (Post-Treatment Follow-Up)  
Study Period 
Post Treatment Follow-upa 
Study Week 
Wk 106 
& 
108 
Wk 
110 
Wk 
117 
Wk 
123 
Wk 
130 
Study Day 
736 
& 
750 
764 
813 
855 
904 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Outpatient Visit 
Xb 
Xb 
X 
Xb 
X 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
Blood Draw (Fasting)e 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialc 
Xd 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
Serum Pregnancy Testf 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplesg 
 
 
X 
 
X 
Urinalysis 
 
Xh 
Xh 
Xh 
Xh 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Legend: 
a 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until apoC-III 
levels return to baseline values 
 
b 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the 
Study Center personnel  
c 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected 
in parallel and analyzed locally.  In the event that both the central and local sample are unreportable (e.g., due to hemolyzed 
or clumped blood samples) another sample must be repeated within 1 week and the result must be reviewed by the 
Investigator and confirmed to be acceptable before dosing can continue.  All platelet count results will be promptly reviewed 
by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose 
pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor 
d 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling 
e 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During 
treatment period urine and blood samples will be collected prior to Study Drug administration.  Does not apply to 24-hour 
PK blood draw 
f 
Females of childbearing potential only 
g 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse 
events (e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of kidney function, 
measurement of antibodies, etc.) in this or subsequent clinical studies of volanesorsen 
h 
Expanded urinalysis (see Appendix B) 


ISIS 304801-CS7 
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Protocol - France 
25 May 2018 
 
76 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be 
performed by dietician or study personnel 
 


ISIS 304801-CS7 
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Amendment 9 
Protocol - France 
25 May 2018 
 
77 
Appendix B 
List of Laboratory Analytes 
Appendix B 
List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be performed on 
stored samples to better characterize the profile of volanesorsen or other similar oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% and 
absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in plasma 
• 
Anti-volanesorsen antibodies 
in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
Troponin I2 
• 
CK-MB2 
• 
Platelet Bound 
Autoantibodies3 
• 
De-lipidated free glycerol 
• 
HbA1c, FPG 
• 
Blood viscosity3 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic examination4 
 
Additional Measures for Expanded 
Urinalysis 
• 
Total protein (quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
Platelet Function 
• 
Platelet aggregation3 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation purposes, 
stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay development and/or 
validation), or to assess other actions of volanesorsen with plasma constituents 
2 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
3 
May be done 
4 
Will be performed on abnormal findings unless otherwise specified 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
78 
Appendix C 
Pharmacokinetic Sampling Schedule 
Appendix C 
Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected prior to 
dosing, and at various times throughout the dosing and post-treatment follow-up period as noted in the 
tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
Post-dose 
Pre-dose Pre-dose Pre-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on Study Day 1.  
Participation is optional 
 
PK Sampling Schedule (Extended Treatment Period) 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Study Day 
D526 
D722 
D813 
Visit Window 
+/- Days 
2 
2 
7 
Time Point 
Pre-dose  
Pre-dose 
Anytime 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
79 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are based 
upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 
 
 
 


ISIS 304801-CS7 
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Amendment 9 
Protocol - France 
25 May 2018 
 
80 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 9 
Protocol - France 
25 May 2018 
 
81 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 
 


Sponsor: 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor, Boston, MA 
02210 
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801)
An Open-Label Study of Volanesorsen Administered Subcutaneously 
to Patients with Familial Chylomicronemia Syndrome (FCS) 
Protocol Amendment 8 – 21 November 2018 
EudraCT No:  2015-003755-21 


ISIS 30480 l-CS7 
Protocol 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 8 
21 November 2018 
An Open-Label Study of Volanesorsen Administered Subcutaneously 
to Patients with Familial Chylomicronemia Syndrome (FCS) 
Protocol Amendment 8 - 21 November 2018 
Protocol History: 
Original Protocol: 
Protocol Amendment 1: 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Protocol Amendment 5: 
Protocol Amendment 6: 
Protocol Amendment 7: 
Approved by: 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
Telephone: 
 
28 August 2015 
2 February 2016 
22 April 2016 
9 May 2016 
6 June 2016 
6 July 2016 
18 November 2016 
7 April 2017 
Akcea Therapeutics, Inc. 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 8 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered Subcutaneously 
to Patients with Familial Chylomicronemia Syndrome (FCS) 
 
Trial Sponsor: 
22 Boston Wharf Road, ,9th Floor 
Boston, MA 02210 
Telephone:
Key Sponsor Contact: 
 
 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
Telephone:
Email:
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court  
Carlsbad, CA 92010 
Date: 
21 November 2018 
Confidentiality Statement 
This document contains confidential information of Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, 
Inc., that must not be disclosed to anyone other than the recipient study staff and members of the 
independent ethics committee, institutional review board, or authorized regulatory agencies.  This 
information cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, 
Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to Patients 
with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 8 
Date: 
21 November 2018 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An Open-
Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS)”, dated 21 November 2018, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on Good 
Clinical Practice (E6) (R2). 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of Akcea Therapeutics, Inc. and Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT ..................................................................................................... 10 
PROTOCOL SYNOPSIS ............................................................................................................ 20 
STUDY DESIGN AND TREATMENT SCHEMA ................................................................... 26 
STUDY GLOSSARY ................................................................................................................... 27 
1. 
OBJECTIVES ................................................................................................................. 29 
2. 
BACKGROUND AND RATIONALE .......................................................................... 29 
2.1 
Overview of Disease .................................................................................................................. 29 
2.2 
Therapeutic Rationale ............................................................................................................... 30 
2.3 
Volanesorsen ............................................................................................................................. 31 
2.3.1 
Mechanism of Action ........................................................................................................ 31 
2.3.2 
Chemistry .......................................................................................................................... 32 
2.3.3 
Preclinical Experience ........................................................................................................ 32 
2.3.4 
Clinical Experience ............................................................................................................. 33 
2.4 
Rationale for Dose and Schedule of Administration ................................................................. 35 
3. 
EXPERIMENTAL PLAN .............................................................................................. 36 
3.1 
Study Design .............................................................................................................................. 36 
3.2 
Number of Study Centers .......................................................................................................... 36 
3.3 
Number of Patients ................................................................................................................... 36 
3.4 
Overall Study Duration and Follow-up ...................................................................................... 36 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 index 
study):  Qualification ......................................................................................................... 36 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification ......... 36 
3.4.3 
Treatment .......................................................................................................................... 36 
3.4.4 
Post-Treatment ................................................................................................................. 37 
3.5 
End-of-Study .............................................................................................................................. 37 
3.6 
Data and Safety Monitoring Board ............................................................................................ 37 
4. 
PATIENT ENROLLMENT ........................................................................................... 37 
4.1 
Screening/Qualification ............................................................................................................. 37 
4.2 
Enrollment ................................................................................................................................. 38 
5. 
PATIENT ELIGIBILITY .............................................................................................. 38 
5.1 
Inclusion Criteria ........................................................................................................................ 38 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-CS16) Index Study 
Roll-over Patients ...................................................................................................................... 39 
6. 
STUDY PROCEDURES ................................................................................................ 42 
6.1 
Study Schedule .......................................................................................................................... 42 
6.1.1 
Qualification (Groups 1 and 2) .......................................................................................... 42 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
6 
6.1.2 
Screening and Qualification (Group 3) .............................................................................. 42 
6.1.3 
Treatment Period .............................................................................................................. 42 
6.1.4 
Extended Treatment Period .............................................................................................. 43 
6.1.5 
Pharmacokinetic (PK) Subgroup ........................................................................................ 43 
6.1.6 
Post-Treatment Period ...................................................................................................... 43 
6.2 
Additional Study Assessments ................................................................................................... 44 
6.2.1 
Laboratory Assessments .................................................................................................... 44 
6.2.2 
Physical Exams and Vital Signs .......................................................................................... 44 
6.2.2.1 
Eruptive Xanthoma ..................................................................................................... 44 
6.2.2.2 
Lipemia Retinalis ........................................................................................................ 44 
6.2.3 
Echocardiography .............................................................................................................. 45 
6.2.4 
ECG.................................................................................................................................... 45 
6.2.5 
MRI................................................................................................................................... 45 
6.2.6 
Quality of Life Assessments ............................................................................................... 45 
6.2.7 
Disease Symptom Diary ..................................................................................................... 45 
6.2.8 
Diet Monitoring ................................................................................................................. 45 
6.2.9 
Family History .................................................................................................................... 45 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2 and 3) ..... 46 
6.3 
Restriction on the Lifestyle of Patients ..................................................................................... 46 
6.3.1 
Contraception Requirements ............................................................................................ 46 
6.3.2 
Other Requirements .......................................................................................................... 47 
7.
STUDY DRUG ................................................................................................................ 47
7.1 
Volanesorsen Description .......................................................................................................... 47 
7.2 
Packaging and Labeling ............................................................................................................. 47 
7.3 
Study Drug Accountability ......................................................................................................... 48 
8.
TREATMENT OF PATIENTS ..................................................................................... 48
8.1 
Volanesorsen Administration .................................................................................................... 48 
8.2 
Other Protocol-Required Drugs ................................................................................................. 48 
8.3 
Other Protocol-Required Treatment Procedures ...................................................................... 48 
8.4 
Treatment Precautions .............................................................................................................. 48 
8.5 
Safety Monitoring Rules ............................................................................................................ 48 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ..................................................................... 49 
8.5.2 
Safety Monitoring for Platelet Count Results .................................................................... 50 
8.5.3 
Safety Monitoring for Minor Bleeding Events ................................................................... 52 
8.5.4 
Safety Monitoring for Constitutional Symptoms .............................................................. 53 
8.5.5 
Safety Monitoring for LDL-C Elevations ............................................................................. 53 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ....................... 53 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ............................................... 54 
8.5.8 
Safety Monitoring for Hyperglycemia ............................................................................... 54 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
7 
8.5.9 
Acute Pancreatitis ............................................................................................................. 55 
8.6 
Stopping Rules ........................................................................................................................... 55 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .................................................................. 55 
8.6.2 
Stopping Rules for Renal Function Test Results ................................................................ 56 
8.6.3 
Stopping Rules for Platelet Count Results ......................................................................... 56 
8.7 
Adjustment of Dose Frequency ................................................................................................. 59 
8.8 
Discontinuation of Study Treatment ......................................................................................... 59 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ........................................ 60 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period............... 60 
8.9 
Withdrawal of Patients from the Study..................................................................................... 60 
8.10 
Concomitant Therapy and Procedures ...................................................................................... 61 
8.10.1 
Concomitant Therapy ........................................................................................................ 61 
8.10.2 
Concomitant Procedures ................................................................................................... 62 
8.11 
Treatment Compliance .............................................................................................................. 62 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ....................... 62 
9.1 
Sponsor Review of Safety Information ...................................................................................... 62 
9.2 
Regulatory Requirements .......................................................................................................... 62 
9.3 
Definitions ................................................................................................................................. 63 
9.3.1 
Adverse Event .................................................................................................................... 63 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ......................................................... 63 
9.3.3 
Serious Adverse Event (SAE).............................................................................................. 63 
9.4 
Monitoring and Recording Adverse Events ............................................................................... 64 
9.4.1 
Serious Adverse Events ..................................................................................................... 64 
9.4.2 
Non-Serious Adverse Events ............................................................................................. 64 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ................................................. 65 
9.4.3.1 
Relationship to the Study Drug .................................................................................. 65 
9.4.3.2 
Severity ....................................................................................................................... 65 
9.4.3.3 
Action Taken with Volanesorsen ................................................................................ 65 
9.4.3.4 
Treatment Given for Adverse Event ........................................................................... 66 
9.4.3.5 
Outcome of the Adverse Event .................................................................................. 66 
9.4.4 
Adjudication Committees .................................................................................................. 66 
9.5 
Procedures for Handling Special Situations............................................................................... 66 
9.5.1 
Abnormalities of Laboratory Tests .................................................................................... 66 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ...................... 67 
9.5.3 
Treatment Errors ............................................................................................................... 67 
9.5.4 
Contraception and Pregnancy ........................................................................................... 67 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 68 
10.1 
Study Endpoints ......................................................................................................................... 68 
10.1.1 
Efficacy Endpoints ............................................................................................................. 68 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
8 
10.1.2 
Safety Endpoints ................................................................................................................ 69 
10.2 
Sample Size ................................................................................................................................ 69 
10.3 
Populations ................................................................................................................................ 69 
10.4 
Definition of Baseline ................................................................................................................ 69 
10.5 
Interim Analysis ......................................................................................................................... 70 
10.6 
Planned Methods of Analysis .................................................................................................... 70 
10.6.1 
Demographic and Baseline Characteristics ....................................................................... 70 
10.6.2 
Safety Analysis ................................................................................................................... 70 
10.6.3 
Efficacy Analysis................................................................................................................. 71 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ................................................................ 71 
10.6.4.1 
Pharmacokinetic Analysis ........................................................................................... 71 
10.6.4.2 
Immunogenicity Analysis ............................................................................................ 72 
11.
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 72
11.1 
Informed Consent ...................................................................................................................... 72 
11.2 
Ethical Conduct of the Study ..................................................................................................... 73 
11.3 
Independent Ethics Committee/Institutional Review Board .................................................... 73 
11.4 
Patient Confidentiality ............................................................................................................... 73 
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................. 74
12.1 
Protocol Amendments ............................................................................................................... 74 
12.2 
Study Termination ..................................................................................................................... 74 
12.3 
Study Documentation and Storage ........................................................................................... 74 
12.4 
Study Monitoring ....................................................................................................................... 75 
12.5 
Language.................................................................................................................................... 75 
12.6 
Compensation for Injury ............................................................................................................ 75 
13.
REFERENCES ................................................................................................................ 77
14.
APPENDICES ................................................................................................................. 80
Appendix A 
Schedule of Procedures ...............................................................................................80 
Appendix B          List of Laboratory Analytes ........................................................................................ 88 
Appendix C           Pharmacokinetic Sampling Schedule ......................................................................... 90 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities .................. 92 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics ...................................................................... 47 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower Limit 
of Normal (x2) or < 100,000/mm3 (x1)* ........................................................................... 52 
Table 3 
Actions in Patients with Low Platelet Count or Drop in Platelet Count ........................... 58 


ISIS 304801-CS7 
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Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and the 
Expected Incidence ........................................................................................................... 63 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms ............................ 30 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ............................................... 32 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen ............................ 34 
 
 


ISIS 304801-CS7 
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Amendment 8 
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10 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment Number: 
8 
Amendment Date: 
21 November 2018 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol ISIS 
304801-CS7 Amendment 7 dated 7 April 2017: 
• 
To add the option for patients to receive a study drug dose reduction as either 300 mg every 
two weeks (prefilled syringe) or 150 mg once-weekly (vial presentation), to clarify that 
discontinuation from the treatment period will be required for any patients who are on a dose 
pause for ≥ 3 months, and to remove the references to landmark visits (if patient stops drug 
treatment then they enter the follow-up period). 
Minor changes (not included in the list of changes below) have been made throughout the protocol to 
correct errors and/or to improve the overall clarity of the original protocol but these changes do not 
impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol, additions are indicated as 
underline and deletions are indicated as strikethrough: 
Protocol 
Section 
Description of Change 
Rationale 
Section 2.3.4 
Clinical 
experience 
Volanesorsen has been evaluated in one Phase 1 study 
and two Phase 2 studies, all double blinded and placebo 
controlled.  The total exposures comprise 99 patients and 
healthy volunteers administered volanesorsen from 50 to 
400 mg subcutaneously up to 3 months (compared to 37 
administered placebo). The clinical experience with 
volanesorsen includes clinical trials in healthy subjects, 
patients with hypertriglyceridemia, FCS, or familial partial 
lipodystrophy. Overall, 431 patients and healthy 
volunteers have taken part in the clinical development 
program, of whom 325 have received at least 1 dose of 
volanesorsen. Ninety-five (95) patients with FCS have 
been enrolled in studies, all showing clinically meaningful 
reductions in plasma triglyceride. Patients with FCS 
continue on treatment in the open-label extension (OLE) 
and triglyceride reductions persist at similar levels as 
reported in earlier studies.  
In the completed Phase 1 and Phase 2 studies, 
volanesorsen was well-tolerated and demonstrated a 
favorable safety profile. There was no clinical or 
laboratory evidence of drug-drug interactions despite 
many patients in the Phase 2 clinical trials receiving 
Update to language regarding 
clinical experience in Phase 1 and 
2 studies and incidence of AEs in 
completed Phase 3 studies and 
update to language regarding 
safety risks of Study Drug. 
 


ISIS 304801-CS7 
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11 
concomitant medications that are known to be associated 
with elevations in hepatic enzymes, such as fibrates and 
statins. There were no volanesorsen-associated 
laboratory abnormalities suggestive of an effect on the 
renal (serum creatinine, proteinuria) or hepatic systems 
(alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], bilirubin). There was a reduction 
(mean reduction < 30%) in platelets in volanesorsen vs. 
placebo with mean nadirs for all doses remaining above 
the lower limit of normal (LLN). The most frequently 
reported adverse events (AEs) were mild, non-
progressive events at the injection site. In Phase 2, a 
single serious adverse event (SAE) of secondary serum 
sickness-like reaction was reported as related to Study 
Drug. 
... 
In clinical studies conducted to date volanesorsen has 
been well-tolerated and has shown a favorable safety 
profile.  There has been no clinical or laboratory evidence 
of drug-drug interactions. 
In the completed studies there have been no 
volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, 
proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase 
[AST], bilirubin).  In Phase 2 studies, there was a mild 
decrease of platelet count associated with volanesorsen 
administration that recovered in the post-treatment period 
and was not associated with platelet-related adverse 
events (AEs).  In the blinded ongoing clinical trials of ISIS 
304801, 2 patients of 142 dosed (as of February 29, 
2016) had a decrease in platelet count to less than 
50,000/mm3 in the absence of major bleeding or 
clinically-relevant non-major bleeding and had Study 
Drug paused as per the monitoring and stopping rules for 
platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of treatment. 
The most frequently observed AEs with volanesorsen 
were local reactions at the injection site.  Local 
cutaneous reactions at the injection site defined as those 
events presenting as either pain, tenderness, erythema, 
pruritus or swelling occurring on the day of injection and 
persisting for at least 2 days were infrequent (~15% of 
injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not 
associated with systemic sequelae. 
In the completed pooled Phase 3 studies (ISIS 304801-
CS6 (hereafter CS6) and ISIS 304801-CS16 (hereafter 
CS16), the most common AEs associated with 
volanesorsen administration were tolerability at the 
injection site and platelet reductions. The majority of the 
injection site AEs were mild, none were severe, and the 
incidence appeared to decrease over time. No deaths 
have been associated with volanesorsen treatment to 
date. No cardiac toxicity was associated with 
volanesorsen treatment. There were no abnormal QTc 
findings and no study-drug related adjudicated major 
adverse cardiac events (MACE). There is no evident 
association between volanesorsen treatment and 
changes in renal or liver functions. 


ISIS 304801-CS7 
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In conclusion,t The safety profile of volanesorsen has 
been well-described in this development program, which 
has identified 3 safety risks: thrombocytopenia (an 
identified risk), constitutional symptoms (flu-like reactions 
and influenza-like illness), and injection site reactions (a 
tolerability signal). Spontaneous, mild to severe 
thrombocytopenia has been described in the FCS patient 
population (Gaudet et al. 2017),but is increased by 
treatment with volanesorsen. Less frequent and less 
pronounced platelet declines were also observed with 
volanesorsen treatment in the hypertriglyceridemic (HTG) 
population of CS16. When fully complied with, frequent 
monitoring for this effect and appropriate dose 
adjustments have been successful both in preventing or 
promptly detecting the occurrence of severe platelet 
declines and often in retaining patients on treatment. 
Section 2.4 
Rationale for 
Dose and 
Schedule of 
Administration 
The dose and schedule selected for this study is 300 mg 
per week for 52 weeks.  The dose of 300 mg per week 
and dose reduction to 300 mg every 2 weeks (delivered 
as either a single 300-mg dose or as 150 mg once-
weekly, respectively) are is supported by both the 
cumulative nonclinical data available to date and the 
Phase and 3 clinical data. 
… 
Non nonclinical findings were not considered to be 
related to the pharmacologic inhibition of apoC-III. 
Language added to specify dose 
reductions  as either 300 mg every 
2 weeks or 150 mg weekly 
according to patient’s tolerability on 
the 300 mg dose, given similar 
extents of triglyceride lowering 
anticipated based on population 
pharmacokinetic/pharmacodynamic 
model based simulations. 
Section 3.4.4 
Post-Treatment  
Patients not participating in the extended treatment 
period will enter the post-treatment evaluation period is 
of 13 weeks and, consists consisting of 7 Study Center 
visits on Weeks 53, 54, 55, 56, 57, 58, and 65 (Weeks 
53, 54, 55, 56, 57, and 58 may be conducted by a home 
healthcare nurse). Patients who complete, or terminate 
early from, the extended treatment period without 
subsequently participating in an expanded access 
program will enter a 13-week post-treatment evaluation 
period consisting of 7 Study Center visits on Weeks 105, 
106, 107, 108, 109, and 110 (which may be conducted by 
a home healthcare nurse), and Week 117 (Appendix A).  
Language added to specify that 
patients who discontinue from 
treatment during treatment period 
of the study, who previously would 
have been followed for landmark 
visits, will now enter into the 13-
week follow-up period 
Section 6.1.3 
Treatment 
Period 
Synopsis, 
Study Visits 
and 
Procedures 
Collection and measurement of race and ethnicity, vital 
signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), adverse 
events (AE), concomitant medication/procedure 
information, lipid panel, blood viscosity, volanesorsen 
plasma concentrations, immunogenicity (IM) testing, 
platelet aggregation, liver/spleen magnetic resonance 
imaging (MRI), ECGs, echocardiograms and quality of 
life assessments will be performed according to the 
schedule of procedures in Appendix A. 
To add a specification that race 
and ethnicity are to be collected. 
Section 6.2.1 
Laboratory 
Assessments 
Should a patient experience constitutional or flu-like 
symptoms after Study Drug administration, investigators 
may consider additional laboratory assessments.  For 
example, plasma and serum samples may be drawn for 
complement (Total C3, C4, C5a and Bb), hsCRP and for 
cytokine analysis. 
To add additional laboratory 
assessments permitted for safety 
purposes 
Section 7.1 
Volanesorsen 
Description 
… 
Volanesorsen (ISIS 304801) is contained in glass 
prefilled syringes (PFS) or in glass vials. 
Table 1 Volanesorsen (ISIS 304801) Characteristics 
To add details of study drug 
preparation to be used in the open-
label extension phase 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
13 
Study Drug 
ISIS 304801 
Prefilled 
Syringe 
ISIS 304801  
Vial* 
Strength 
300 mg 
200 mg 
Volume / 
Formulation 
1.5 mL 
200 mg/mL ISIS 
304801 
1.0 mL 
200 mg/mL ISIS 
304801 
Dose 
300 mg / 1.5 mL  
150 mg / 0.75 
mL 
Route of 
Administration 
Subcutaneous 
injection 
Subcutaneous 
injection 
Section 7.3 
Study Drug 
Accountability 
All used syringes or vials must be disposed of as per the 
site’s hazardous waste destruction policy. 
Specified disposal of study drug 
preparation to be used in the open-
label extension phase 
Section 8.1 
Volanesorsen 
Administration 
For each individual patient, volanesorsen  will be 
administered subcutaneously as a single 1.5 mL 300 mg 
injection once weekly for Weeks 1-52, and patients will 
continue to receive Study Drug as a single 300 mg/1.5 
mL injection once-weekly for Weeks 53-104 of the study.  
Patients entering this ISIS 304801-CS7 study on a 
reduced dose or dose frequency of Study Drug 
(volanesorsen), for safety or tolerability reasons in their 
index study (ISIS 304801-CS6 or ISIS 304801-CS16), 
will receive a reduced dose or dose frequency of 
volanesorsen for continued safety or tolerability as 
outlined in Sections 8.5 and 8.6.  Patients on dose 
reduction will receive either 300 mg/1.5 mL injections 
every 2 weeks or 150 mg/0.75 mL injections 
once-weekly.  Treatment with a 150 mg dose during the 
study will use the glass vials containing 200 mg/mL of 
volanesorsen.  Patients entering this CS7 study having 
dose or dose frequency reduced in the CS16 index study 
after 13 weeks of treatment, as outlined in CS16 
Amendment 4 Section 8.7, can receive the 300 mg once 
weekly dose of volanesorsen. Treatment 
Patients should receive 1 dose per week, unless on a 
dose reduction of 300 mg every 2 weeks, with weeks 
always defined relative to Study Day 1.   
… 
Added language detailing dose 
reduction options.  
Section 8.5.2 
Safety 
Monitoring for 
Platelet Count 
Results 
Monitor every 1 week unless otherwise specified.  In 
addition, platelet function may be evaluated at any time 
during the study by aggregometry, using an approved 
point-of-care diagnostic device in some patients.  This 
additional functional testing may be performed at 
selected study centers. 
… 
Due to the 1 to 2-year study duration, it is anticipated that 
patients may undertake travel including vacations, which 
may impede weekly platelet monitoring.  In some 
situations, it may be possible to arrange for local 
laboratory testing or use of the home healthcare service 
at their temporary location.  The intent is to maintain 
weekly platelet monitoring and treatment where possible, 
as well as Investigator site contact with the study 
patients.  However, if the above options are not possible, 
a temporary interruption of study treatment will be 
Additional point-of-care platelet 
function testing may be conducted 
on patients at participating study 
centers. 
 
Included an additional blood draw 
to assess platelet count prior to any 
travel that would result in missing a 
weekly monitoring visit.   


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
14 
planned with a platelet count drawn within 3-5 days prior 
to departure and a prompt blood draw upon the patient’s 
return which must be reported and reviewed by the 
Investigator prior to the patient resuming treatment. 
 
Patients on dose pause should be monitored as per the 
platelet monitoring rules outlined in Section 8.8.1 until 
Study Drug administration is resumed. 
8.5.4 Safety 
Monitoring for 
Constitutional 
Symptoms 
Should a patient experience constitutional or flu-like 
symptoms after Study Drug administration, investigators 
may consider additional laboratory assessments.  For 
example, plasma and serum samples may be drawn for 
complement (Total C3, C4, C5a and Bb), hsCRP, and for 
cytokine analysis. 
To add additional laboratory 
assessments permitted for safety 
purposes 
Section 8.6.3 
Stopping Rules 
for Platelet 
Count Results 
In the event of any platelet count less than 50,000/mm3, 
or a platelet count less than 75,000/mm3 that occurs 
while the patient is treated at 300 mg every 2 weeks or 
150 mg once-weekly then treatment of a patient with 
volanesorsen will be stopped permanently. 
… 
In the event of a platelet count less than 75,000/mm3, 
and in the absence of major bleeding or clinically-relevant 
non-major bleeding (defined below; Schulman et al. 
2005), treatment of a patient with volanesorsen should be 
suspended temporarily until the platelet count has 
recovered to ≥ 100,000/mm3.  If dosing is continued 
treatment is reinitiated, it should be at a reduced dose 
frequency of 300 mg every 2 weeks or 150 mg once-
weekly every week(refer to Section 8.7). 
 
Table 3 Actions in Patients with Low Platelet Count or 
Drop in Platelet Count 
To provide clarification to the 
platelet safety monitoring rules, 
including dose reduction options. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
15 
Platelet 
Count on 
Rx 
Drug Dose 
Monitoring 
Study Drug 
administration is 
contingent on the 
availability of the 
immediately 
preceding test 
result.  An 
interpretable 
platelet value 
must be available 
within 7 days prior 
to treatment.  
Only the study 
doctor or qualified 
designee can 
authorize 
continued Study 
Drug 
administration 
based on an 
acceptable 
platelet value.  
Patients should 
not administer a 
dose until they 
have been 
contacted by their 
study doctor or 
designee and told 
that it is 
acceptable to 
dose.  
Authorization to 
dose must be 
documented in 
the patient’s 
medical records. 
Monitor every 1 
week unless 
otherwise 
specified 
In addition, 
platelet function 
may be evaluated 
during the study 
by aggregometry, 
using an 
approved point-
of-care diagnostic 
device, in some 
patients.  This 
additional 
functional testing 
may be 
performed at 
selected study 
centers. 
Patients on dose 
pause should be 
monitored as per 
the platelet 
monitoring rules 
outlined in 
Section 8.8.1 until 
Study Drug 
administration is 
resumed. 
Obtain additional 
lab tests 
(Table 2) if 
2 occurrences 
(consecutive or 
non-consecutive) 
of platelet count  
140K - 
> 100K/mm3 or 1
occurrence of
platelet count ≤
100K/mm3.  Labs
only need to be
performed once.
Labs may be
collected over
multiple visits, if
blood
requirements are
a concern, as per
Investigator
discretion.


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
16 
> 100K/mm3 
Once -weekly 300 
mg Study Drug 
administration 
 
100K/mm3 - 
> 75K/mm3 
Permanently 
reduce dose 
frequency to 
300 mg every 
2 weeks or 
150 mg once-
weekly.  
 
75K/mm3 
- > 50K/mm3 
• 
If occurs 
while on dose 
of 300 mg 
every 2 
weeks or 
150 mg once-
weekly then 
permanently 
discontinue 
Study Drug, 
otherwise 
dose pause. 
If dose pause 
is ≥ 3 months 
then patient 
must 
discontinue 
treatment 
and enter the 
follow up 
period. 
• 
When platelet 
count returns 
to 
> 100K/mm3 
restart 
treatment at 
dose 
frequency of 
300 mg every 
2 weeks or 
150 mg once-
weekly only if 
approved by 
in 
consultation 
with the 
Sponsor 
Medical 
Monitor 
Monitor every 2-3 
days until 
2 successive 
values are > 
75K/mm3 then 
monitor every 1 
week 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/ 
anticoagulant 
medication 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
17 
≤ 50K/mm3 
Permanently 
discontinue Study 
Drug and the 
patient will enter 
the follow up 
period. 
• Monitor daily 
until 2 
successive 
values show 
improvement 
then monitor 
every  
2-3 days until 
2 successive 
values are 
> 75K/mm3 then 
monitor every 1 
week 
• Patient should 
be evaluated by 
a hematologist 
to provide 
diagnostic and 
therapeutic 
management 
• Steroids 
recommended*.  
It is strongly 
recommended 
that, unless the 
patient has a 
medical 
contraindication 
to receiving 
glucocorticoids, 
the patient 
receives 
glucocorticoid 
therapy to 
reverse the 
platelet decline.   
• Monitor 
triglyceride 
levels weekly 
and continue 
AE monitoring 
during steroid 
therapy 
Discontinue 
antiplatelet 
agents/ NSAIDS/ 
anticoagulant 
medication while 
platelet count is 
< 50K/mm3 if 
possible 
Section 8.7 
Adjustment of 
Dose 
Frequency 
Other dose adjustments, including dose interruptions, 
and/or decreasing the dose to 150 mg once-weekly or 
the dose frequency to 300 mg every 2 other weeks will 
be allowed for safety and tolerability. 
Addition of dose reduction options 
to allow for safety and tolerability 
 
Discontinuation of patients from the 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
18 
… 
Patients may be dose paused in response to AEs after 
consultations with, and the Study Medical Monitor is 
informed. If a patient is dose paused for ≥ 3 months, he 
or she is considered to have discontinued treatment and 
should enter the 13-week post-treatment follow-up 
period. 
study who have been on dose 
pause and off study drug for >3 
months. 
 
Section 8.8 
Discontinuation 
of Study 
Treatment 
A patient must permanently discontinue study treatment 
for any of the following: 
… 
•The patient is dose-paused for ≥ 3 months then they 
must discontinue the treatment period and enter the 
follow-up period. 
Added new treatment 
discontinuation criterion consistent 
with other protocol changes. 
Section 8.8.1 
Follow-up Visits 
for Early 
Termination 
from Treatment 
Period 
Patients should be strongly encouraged to attend 
applicable landmark visits at Weeks 12, 13, 25, 26 and 
50, 52 of Randomized Treatment period (calculated 
based on the time elapsed since Day 1) and at Weeks 
64, 65, 77, 78 and 102, 104 of OLE period to collect 
fasting lipid panels and conduct safety assessments in 
accordance with the schedule of procedures in Appendix 
A. Any patient who discontinues treatment after Week 44 
should also be strongly encouraged to attend a final 
follow-up visit (Week 65 visit assessments) 
approximately 13 weeks after their last dose of Study 
Drug, in addition to the applicable landmark visits. 
 
… 
A patient who discontinues early from treatment with 
stable platelet counts above the LLN at the time of 
treatment discontinuation will have platelet counts drawn 
every 2 weeks after discontinuing Study Drug for the first 
6 weeks after the last dose of Study Drug.  A subsequent 
platelet count should then be taken after an additional 6 
weeks so that patients are monitored for at least 12 
weeks after discontinuing Study Drug. 
Removal of language around 
landmark visits as patients who 
stop treatment now enter a post-
treatment follow-up period 
 
Provides guidance for platelet 
monitoring in the post-treatment 
follow-up period.  
Section 13 
REFERENCES 
Gaudet D, Baass A, Tremblay K, et al. Natural History 
(up to 15 years) of Platelet Count in 84 Patients with 
Familial Hyperchylomicronemia Due to Lipoprotein 
Lipase Deficiency. Journal of Clinical Lipidology 2017; 
11(3): 797-798. 
Addition of reference 
Section 14 
APPENDICES 
Appendix A Schedule of Procedures 
Added platelet function analysis to extended treatment 
period table. 
Footnote i: Genetic testing can be conducted for study 
qualification (Group 2 [ISIS 304801-CS16 roll-over 
patients] and Group 3); genetic testing will only be 
conducted if allowed in the geographic region and only 
after the patient has given specific written informed 
consent for genetic testing. A blood sample for potential 
gene sequencing may be collected at timepoints other 
than Screening or Qualification Visits.Footnote g: May be 
done 
Clarification that blood sampling for 
gene sequencing may occur during 
the study. 
Indication that platelet function may 
be assessed. 
 
Section 14 
APPENDICES 
Appendix B List of Laboratory Analytes 
Platelet Function 
Platelet aggregation3 
Platelet function5 
Addition of laboratory analyte to 
measure platelet function. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
19 
Footnote 5: May be done using a point-of-care device on 
site. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
20 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of treatment and extended treatment with 
volanesorsen in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will have the option of 
participating in an expanded access program or continuing treatment for up to 
an additional 52 weeks until an expanded access program is approved and 
available in their country.  Patients not participating in an expanded access 
program will enter a 13-week post-treatment evaluation period 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order 
to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of 
the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical 
history. Note: testing of LPL activity should not be performed to 
confirm eligibility for the study 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
21 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label study  
4. 
Able and willing to participate in a 65-week studyInclusion Criteria: 
Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), 
post-menopausal (defined as 12 months of spontaneous amenorrhea in 
females > 55 years of age or, in females ≤ 55 years, 12 months of 
spontaneous amenorrhea without an alternative medical cause and FSH 
levels in the postmenopausal range for the laboratory involved), 
abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 
6.3.1) from time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual relations with 
a female of child-bearing potential, patient is utilizing an acceptable 
contraceptive method (refer to Section 6.3.1) from the time of signing the 
informed consent form until 13 weeks after the last dose of Study Drug 
administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with 
the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial and withdrawal are not acceptable 
methods of contraception 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2  
(ISIS 304801-CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the opinion 
of the Investigator would make the patient unsuitable for enrollment, or could 
interfere with the patient participating in or completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3) 
Exclusion Criteria for Group 3 (patients who did not participate in an index study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or 
addition of new medication within 12 weeks of screening [with the 
exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. 
Active pancreatitis within 4 weeks prior to screening Exclusion 
Criteria for Group 3 (patients who did not participate in an index study) 
Continued 
4. History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of screening 
5. Any of the following laboratory values at Screening 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Platelet count < lower limit of normal (LLN) for the central 
laboratory (i.e., < 140,000/mm3) 
d. 
Cardiac Troponin I > ULN at Screening 
e. 
LDL-C > 130 mg/dL at Screening 
f. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
 


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PROTOCOL SYNOPSIS Continued 
 
11. 
Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated 
 
12. Treatment with another investigational drug, biological agent, or device 
within 1 month of screening, or 5 half-lives of investigational agent, whichever 
is longer  
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) Continued 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to screening and dose and 
regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
screening unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to screening and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to screening and dose and regimen expected to remain 
constant during the treatment period 
f. Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening and dose and regimen expected to 
remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to screening or planned during 
the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening 
(Occasional or intermittent use of over-the-counter medications will be 
allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of 
> 499 mL within 60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or the 
Sponsor would make the patient unsuitable for inclusion, or could 
interfere with the patient participating in or completing the study 


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PROTOCOL SYNOPSIS Continued 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 and 3 studies (Section 2.4) which included a subset of patients 
with FCS.  The same dose of 300 mg once weekly will be used in this open-
label study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up to 
2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A 
• 
Group 3 patients (did not participate in an index study):  An up to 
8-week screening and qualification period, including a diet 
stabilization period of at least 6 weeks (screening and diet 
stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease 
management prior to screening).  Please refer to Section 6.1.2 and 
Appendix A 
• 
All patients: 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
Option to participate in an extended treatment period (up to an 
additional 52 weeks) 
o 
A 13-week post-treatment evaluation period or expanded 
access program 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of race and ethnicity, vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and 
urinalysis), adverse events (AE), concomitant medication/procedure 
information, lipid panel, blood viscosity, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, platelet aggregation, liver/spleen magnetic 
resonance imaging (MRI), ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in 
Appendix A.  Dietary counseling will be repeated at intervals throughout the 
treatment and follow-up period and a daily food/drink diary will be completed 
for the week prior to each quarterly visit by each patient.  Following the 
Week 52 visit, patients will have the option of participating in an expanded  
 
 


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PROTOCOL SYNOPSIS Continued 
 
access program or continuing treatment for up to an additional 52 weeks until 
an expanded access program is approved and available in their country.  
Patients not participating in an expanded access program will enter the 13-
week post-treatment evaluation period. 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic  


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PROTOCOL SYNOPSIS Continued 
 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Akcea Therapeutics, Inc.  
Collaborator 
Ionis Pharmaceuticals, Inc. 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
SCREENING PERIOD 
Weeks -8 to -2 (Group 3 patients only) 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION (ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety 
assessments.  PK and PD/efficacy 
assessments at specified time points 
POST-TREATMENT 
EVALUATION PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD 
assessments 
Patients will have 
the option of 
participating in an 
expanded access 
program or 
continuing 
treatment for up to 
an additional 52 
weeks until an 
expanded access 
program is 
approved and 
available in their 
country


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
glycosylphosphatidylinositol-anchored hdl-binding protein 1 
HAPI 
heritability and phenotype intervention 
HbA1c 
glycated hemoglobin 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein-cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
intermediate density lipoprotein 
IEC 
Independent Ethics Committee 


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IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein-cholesterol 
LMF1 
lipase maturation factor 1 
LPL 
lipoprotein lipase 
MACE 
major acute cardiovascular event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
no-observed-adverse-effect level 
non-HDL-C 
non-high-density lipoprotein-cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
triglyceride-rich lipoproteins 
ULN 
upper limit of normal 
VLDL 
very-low-density lipoprotein 
VLDL-C 
very-low-density lipoprotein-cholesterol 
VLDL-TG 
lipoprotein-triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of treatment and extended treatment 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare autosomal 
recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above normal 
(1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 15-20% of daily 
calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in infancy or childhood with 
frequent and severe abdominal pain, repetitive colicky pain, repeated episodes of potentially fatal acute 
pancreatitis, and failure to thrive (Brunzell 1999-2011; Tremblay et al. 2011).  Physical examination 
frequently reveals eruptive xanthomas, lipemia retinalis and hepatosplenomegaly, and plasma from 
patients appears lactescent, interfering with determination of other laboratory parameters (Tremblay et 
al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of chylomicronemia.  
Clinical diagnosis would include evidence of clinical features of chylomicronemia syndrome and 
secondary causes such as uncontrolled type 1 or type 2 diabetes mellitus (T2DM), hypothyroidism, poor 
diet, alcohol use, nephrotic syndrome or use of associated medications should be ruled out.  The 
diagnosis of FCS may be made more specifically by genotyping or confirmation of very low or absent 
lipoprotein lipase (LPL) enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described above, 
being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent episodes of 
acute pancreatitis, these patients may also develop chronic pancreatitis and signs of exocrine or 
endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  While the 
pathophysiology underlying chylomicron-related pancreatitis has not been completely elucidated, 1 
hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to pancreatic lipase, 
with the subsequent release of free fatty acids through the hydrolysis of chylomicron-associated TGs.  
High concentrations of free fatty acids are thought to damage pancreatic cells leading to emergent 
pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, skeletal 
muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL is regulated by a 
number of key genes, and loss-of-function mutations in one of these genes, or the LPL gene itself, results 
in FCS (Surendran et al. 2012).  In addition to loss of function mutations, null mutations, and nonsense 
mutations in the LPL gene, other genes currently identified in FCS patients, and known to directly 
influence LPL activity include: apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); 
apolipoprotein A-V (APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 


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(LMF1), a transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary endothelial cell 
protein that provides a platform for LPL-mediated processing of chylomicrons (Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major regulator 
of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels (Chan et al. 2008).  It is 
a component of triglyceride-rich lipoproteins (TRLs) and a potent inhibitor of LPL (Lemieux et al. 2003).  
At higher concentrations apoC-III also inhibits hepatic lipase activity (Kinnunen and Ehnolm 1976), an 
enzyme which plays an important role in the conversion of dense very-low-density lipoprotein (VLDL) to 
intermediate density lipoprotein (IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of 
HDL (Brown et al. 2010).  In addition, increased apoC-III content adversely affects apoE-mediated 
hepatic uptake of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are 
associated with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the development of 
hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, CETP = 
cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, HL = hepatic lipase, IDL = 
intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, LDL = low-density lipoprotein, LDLr 
= LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated receptor, SR-B1 = scavenger receptor B-1, TG = 
triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a prominent 
component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in inhibiting LPL, apoC-III inhibits 
TRL remnant (TG-depleted remnant lipoprotein) uptake by hepatic lipoprotein receptors by steric 
inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; Pollin et 
al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was identified in the 
heritability and phenotype intervention (HAPI) heart study in Old Order Amish that results in lower 
plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and reduced atherosclerosis (Pollin et al. 
2008).  In another study involving a group of 214 Ashkenazi Jews of advanced age (had passed or nearly 
reached 100 years of age), genotype analysis revealed a polymorphism in the apoC-III gene (APOC3-
641CC genotype) with a clear pattern of age-dependent frequency that was associated with significantly 
lower levels of apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 
2006).  In contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) Asian 
Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have significantly 
higher plasma apoC-III and TG levels, and decreased ability to clear postprandial plasma TG from the 
circulation.  Taken together, the available data strongly support the development of a therapy that 
reduces plasma apoC-III levels in order to reduce the very high circulating triglyceride and chylomicron 
levels that are accompanied by increasing risk for acute pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients who have 
no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to date on apoC-III 
function, potential mechanisms that explain how apoC-III inhibition results in triglyceride reduction in 
FCS patients include:  (1) enhancing the very small residual amounts of LPL activity that these patients 
may have, below the limit of detection of the assay in many cases (2) potentially enhanced activity of 
other lipases also involved in the metabolism and breakdown of TGs, such as hepatic lipase or 
endothelial lipase (Kinnunen and Ehnolm 1976), and (3) apoC-III interaction with Apolipoprotein E 
(apoE), an important factor in liver reuptake of lipid particles by blocking apoE-mediated uptake of lipid 
particles in the liver (Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated 
uptake of lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or 
all of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential to 
manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human apoC-III.  
It is complementary to a region within the 3ʹ untranslated region of the apoC-III messenger ribonucleic 
acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  The hybridization (binding) of 
volanesorsen to the cognate mRNA, results in the RNase H1-mediated degradation of the apoC-III 


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mRNA, thus preventing production of the apoC-III protein.  Maximal antisense-mediated reduction of 
target mRNA levels is typically greater than 90% of control levels in sensitive tissues (Crooke and 
Bennett 1996; Zhang et al. 2010).  Furthermore, reduction in target mRNA levels using this approach 
correlates directly with a subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are connected 
sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen (Figure 2) is 
complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the apoC-III mRNA 
transcript at base position 489-508.  Structurally, the oligonucleotide has 3 regions.  Two (2) of them, 
the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are composed of 2ʹ-O-(2-
methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified nucleotides confer (1) increased 
affinity to the target mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to 
exonucleases and endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and (3) 
amelioration of some of the high dose toxicities thereby resulting in an improved safety profile 
compared to first generation antisense drugs containing phosphorothioate modified 
oligodeoxynucleotides (DNA) (Henry et al. 2000).  The third region, the central portion of the 
oligonucleotide, is composed of 10 oligodeoxynucleotides.  This chimeric design is called a MOE-
Gapmer, and volanesorsen employs this chimeric structure to enable use of the RNase H1-mechanism 
for antisense activity.  This is because while the 2ʹ-MOE modification confers increased stability and 
affinity, it does not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides 
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 2ʹ-
alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; Monia et al. 1993).  
By limiting the 2ʹ-MOE modification to nucleotides flanking the phosphorothioate oligodeoxynucleotide 
core, the beneficial attributes of the 2ʹ-MOE chemistry are preserved while also retaining RNase H1 
recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III mRNA as 
well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in several species, 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive) 
A  G  C 
T
T 
C  T 
T G T
C C A G C
T T T A T 
Phosphorothioate 
Backbone 


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including human apoC-III transgenic mice, and other rodent and monkey models.  Treatment with 
volanesorsen also resulted in reduced VLDL and chylomicron TG and reduced postprandial TG in 
hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of treatment 
followed by up to a 20-week recovery period are complete.  The preclinical toxicology program for 
volanesorsen consists of single dose safety pharmacology studies in the monkey (cardiovascular) and 
mouse (neurobehavioral and pulmonary assessment studies), in vitro and in vivo genetic toxicity 
assessment, repeat dose fertility and/or developmental reproductive toxicology studies in the mouse 
and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with those 
expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects consistent with drug 
accumulation in tissues in rodents and monkeys, species-dependent proinflammatory response in 
rodents and monkeys and complement activation and reductions in platelet counts in the monkey.  In 
the mouse and monkey general toxicity studies, reduction of hepatic apoC-III mRNA (> 75%) was not 
associated with any findings that could be considered related to the pharmacologic inhibition of apoC-III 
for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent species 
are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, these effects on 
the heart were not observed in the monkey chronic toxicity studies even at the highest doses tested 
where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to be 
rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) and was 
non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or embryo/fetal 
development in the mouse or rabbit reproductive toxicity studies.  In these studies, volanesorsen was 
detected in placental tissue but not in fetal tissue indicating that little, if any, drug was able to cross the 
placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in males and 47% in females) also did not 
affect fertility or cause untoward effects on embryo/fetal development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be found in the 
volanesorsen Investigator’s Brochure. 
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found in the 
volanesorsen Investigator’s Brochure.  A summary is included below. 
The clinical experience with volanesorsen includes clinical trials in healthy subjects, patients with 
hypertriglyceridemia, FCS, or familial partial lipodystrophy. Overall, 431 patients and healthy volunteers 


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have taken part in the clinical development program, of whom 325 have received at least 1 dose of 
volanesorsen. Ninety-five (95) patients with FCS have been enrolled in studies, all showing clinically 
meaningful reductions in plasma triglyceride. Patients with FCS continue on treatment in the open-label 
extension (OLE) and triglyceride reductions persist at similar levels as reported in earlier studies.  
In the completed Phase 1 and Phase 2 studies, volanesorsen was well-tolerated and demonstrated a 
favorable safety profile. There was no clinical or laboratory evidence of drug-drug interactions despite 
many patients in the Phase 2 clinical trials receiving concomitant medications that are known to be 
associated with elevations in hepatic enzymes, such as fibrates and statins. There were no volanesorsen-
associated laboratory abnormalities suggestive of an effect on the renal (serum creatinine, proteinuria) 
or hepatic systems (alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin). There 
was a reduction (mean reduction < 30%) in platelets in volanesorsen vs. placebo with mean nadirs for all 
doses remaining above the lower limit of normal (LLN). The most frequently reported adverse events 
(AEs) were mild, non-progressive events at the injection site. In Phase 2, a single serious adverse event 
(SAE) of secondary serum sickness-like reaction was reported as related to Study Drug. All clinical trials 
of volanesorsen have shown large and clinically meaningful reductions in fasting plasma apoC-III and TG 
(~80% and 70%, respectively, mean reduction from baseline with 300 mg dose) with a very high degree 
of consistency of response between the different patient groups.  This includes healthy volunteers, 
patients with moderate to severe hypertriglyceridemia not on background TG-lowering therapy, 
patients with moderate to severe hypertriglyceridemia on a background stable fibrate therapy (Gaudet 
et al. 2015), patients with FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an open-label 
fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 3 patients achieved 
TG levels below or close to 500 mg/dL during the treatment period out to Day 92 (Figure 3).  Two (2) of 
the FCS patients had an absolute reduction in fasting TG in excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 


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In the completed pooled Phase 3 studies (ISIS 304801-CS6 (hereafter referred to as CS6) and ISIS 
304801-CS16 (hereafter referred to as CS16), the most common AEs associated with volanesorsen 
administration were tolerability at the injection site and platelet reductions. The majority of the 
injection site AEs were mild, none were severe, and the incidence appeared to decrease over time. No 
deaths have been associated with volanesorsen treatment to date. No cardiac toxicity was associated 
with volanesorsen treatment. There were no abnormal QTc findings and no study-drug related 
adjudicated major adverse cardiac events (MACE). There is no evident association between 
volanesorsen treatment and changes in renal or liver functions. 
The safety profile of volanesorsen has been well-described in this development program, which has 
identified 3 safety risks: thrombocytopenia (an identified risk), constitutional symptoms (flu-like 
reactions and influenza-like illness), and injection site reactions (a tolerability signal). Spontaneous, 
mild-to-severe thrombocytopenia has been described in the FCS patient population (Gaudet et al. 2017) 
but is increased by treatment with volanesorsen. Less frequent and less pronounced platelet declines 
were also observed with volanesorsen treatment in the hypertriglyceridemic (HTG) population of CS16. 
When fully complied with, frequent monitoring for this effect and appropriate dose adjustments have 
been successful both in preventing and promptly detecting the occurrence of severe platelet declines 
and often in retaining patients on treatment. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 300 mg per 
week and dose reduction to 300 mg every 2 weeks (delivered as either a single 300 mg dose or as 
150 mg once-weekly, respectively) are supported by both the cumulative nonclinical data available to 
date and the Phase 2 and 3 clinical data.  In nonclinical studies, volanesorsen treatment-related effects 
in rodents and monkeys were consistent with drug accumulation in tissues and also include species-
specific proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) was 
defined by the cumulative clinical pathology results and histopathology data which provide an adequate 
clinical margin.  Nonclinical findings were not considered to be related to the pharmacologic inhibition 
of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 300 mg in 
patients with high triglycerides (including type 2 diabetes patients and administration in combination 
with fibrates and statins) with the most common AEs being local to the injection site and predominantly 
mild.  A pooled analysis of safety for the Phase 2 studies did not demonstrate any clear difference in 
safety or tolerability between the different doses tested (100 mg, 200 mg, and 300 mg per week for 13 
weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, apoC-III, 
with a clear difference in the TG-lowering effect between the different doses in the 100 mg to 300 mg 
dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 2′-MOE-


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modified ASOs that have been administered intravenously and subcutaneously in multiple clinical 
studies at doses up to 1200 mg and for treatment durations that exceed 24 months (Santos et al. 2015). 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or  
ISIS 304801-CS16 index studies 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients will have the option of participating in an expanded access 
program or continuing treatment for up to an additional 52 weeks until an expanded access program is 
approved and available in their country.  Patients not participating in an expanded access program will 
enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 index study):  
Qualification 
A period of up to 2 weeks (unless approved by the Sponsor) is given to complete qualification 
assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and Appendix A. 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification 
An up to 8-week screening and qualification period, including a diet stabilization period of at least 6 
weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if the patient is 
following a diet for optimal control of TGs and disease management prior to screening.  Please refer to 
Section 6.1.2 and Appendix A. 
3.4.3 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for assessments at 
specified intervals throughout the 52-week treatment period as detailed in the Schedule of Procedures 


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(Appendix A).  During the treatment period, volanesorsen is administered by SC injection once 
weekly.treatmenttreatment 
3.4.4 
Post-Treatment 
Patients not participating in the extended treatment period will enter the post-treatment evaluation 
period of 13 weeks, consisting of 7 Study Center visits on Weeks 53, 54, 55, 56, 57, 58, and 65 
(Weeks 53, 54, 55, 56, 57, and 58 may be conducted by a home healthcare nurse). Patients who 
complete, or terminate early from, the extended treatment period without subsequently participating in 
an expanded access program will enter a 13-week post-treatment evaluation period consisting of 7 
Study Center visits on Weeks 105, 106, 107, 108, 109, and 110 (which may be conducted by a home 
healthcare nurse), and Week 117 (Appendix A). 
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, tolerability 
and efficacy data collected on volanesorsen during this study.  Based on its ongoing assessment of the 
safety and tolerability of volanesorsen, the DSMB will provide recommendations to the Sponsor for 
modifying, stopping or continuing the study as planned.  Details on the safety assessments, frequency of 
review and meeting schedules are outlined in the DSMB Charter and/or the statistical analysis plan 
(SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Screening/Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the protocol, 
informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-specific 
procedures or evaluations related to this open-label study are performed.   
Groups 1 and 2 (Qualification):  During the qualification period, the eligibility of the patient to enroll in 
the open-label study will be determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-
CS16 studies may be used for qualification.  A period of up to 2 weeks after completion of the ISIS 
304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was assigned 
to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient identification 
number will be used to identify the patient throughout the extension trial and must be used on all study 
documentation related to that patient.  The patient identification number must remain constant 
throughout the extension trial. 
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered enrolled 
into the study and will be assigned a unique screening number before any study procedures, including 


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screening procedures, are performed.  At the time of enrollment, patients will be assigned a unique 
patient identification number.  This number will be used to identify the patient throughout the trial and 
must be used on all study documentation related to that patient.  The screening number and patient 
identification number must remain constant throughout the entire trial.  In the event the patient is re-
consented and re-screened the patient must be given a new screening number.  Screening numbers and 
patient identification numbers, once assigned, will not be re-used. 
4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all Screening (Group3) and 
qualification assessments have been completed and after the Investigator has verified that they are 
eligible per criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria within 2 
weeks of Study Day 1, or at the time point specified in the individual eligibility criterion listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index studies) 
with an acceptable safety profile, per Sponsor and Investigator judgement. 
Groups 2 and 3:  Patients must also meet the following criteria in order to enter into the open-
label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a creamy 
top layer after ultracentrifugation of a fasting blood sample) or documentation of fasting TG 
measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
supported by documentation of at least 1 of the following: 
• 
Confirmed homozygote, compound heterozygote or double heterozygote for known 
loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, GPIHBP1, or 
LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical history.  Note: testing of 
LPL activity should not be performed to confirm eligibility for the study 
c. Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the  
 
ISIS 304801-CS16 index study 
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label study 
4. Able and willing to participate in a 65-week study 


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5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal (defined 
as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 
years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH 
levels in the postmenopausal range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an acceptable contraceptive 
method (refer to Section 6.3.1) from time of signing the informed consent form until 13 
weeks after the last dose of Study Drug administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of child-
bearing potential, patient is utilizing an acceptable contraceptive method (refer to Section 
6.3.1) from the time of signing the informed consent form until 13 weeks after the last dose 
of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred 
and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are 
not acceptable methods of contraception 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-CS16) Index Study 
Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study (Section 6.3). 
Exclusion Criteria for Group 3 (patients who did not participate in an index study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of screening [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of the 
Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening 


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4. History within 6 months of screening of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack or 
unstable congestive cardiac failure requiring a change in medication or major surgery within 3 
months of screening 
5. Any of the following laboratory values at Screening 
a. Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and documentation 
of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine dipstick.  In 
the event of a positive test eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on urine 
dipstick.  In the event of a positive test eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after discussion with Sponsor 
Medical Monitor) 
c. Platelet count < LLN for the central laboratory (i.e., < 140,000/mm3) 
d. Cardiac Troponin I > ULN at Screening 
e. LDL-C > 130 mg/dL at Screening 
f. 
Any other laboratory abnormalities which, in the opinion of the Investigator or the Sponsor, 
would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in coagulation 
parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed 
prior to Study Day 1 


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10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma 
in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1-month of 
screening, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable dose for at 
least 3 months prior to screening and dose and regimen expected to remain constant during 
the treatment period.  Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening unless 
approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable dose 
for at least 3 months prior to screening and dose and regimen expected to remain stable 
throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to screening 
and dose and regimen expected to remain constant during the treatment period 
f. 
Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on a 
stable dose for at least 4 weeks prior to screening and regular clinical monitoring is 
performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to 
screening and dose and regimen expected to remain constant during the treatment period 
i. 
Plasma apheresis within 4 weeks prior to screening or planned during the study 
j. 
Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 60 days of 
screening 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or placebo) 


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17. Have any other conditions, which, in the opinion of the Investigator or the Sponsor would make 
the patient unsuitable for inclusion, or could interfere with the patient participating in or 
completing the study 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification (Groups 1 and 2) 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  An 8-week period, including a diet stabilization period of at least 6 weeks 
(screening and diet stabilization period may be reduced, per Sponsor approval, if the patient is following 
a diet for optimal control of TGs and disease management prior to screening) is given to perform the 
screening evaluations.  The qualification assessments will be performed at Week -2 to -1, ideally after 
patient eligibility has been determined, and on Study Day 1.  Abnormal screening results may be 
retested for review by the Study Medical Monitor for eligibility purposes 
6.1.3 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through the last 
patient’s Week 13 visit of the open-label study or until results from the database locks for the ISIS 
304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 5 
times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be administered 
once weekly unless the patient is on a biweekly treatment schedule for safety reasons (Section 8.1).  
Collection and measurement of race and ethnicity, vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), AEs, concomitant medication/procedure information, 
lipid panel, blood viscosity, volanesorsen plasma concentrations, immunogenicity (IM) testing, platelet 
aggregation, liver/spleen MRI, ECGs, echocardiograms and quality of life assessments will be performed 
according to the schedule of procedures in Appendix A.  Adverse events at the injection site should be 
collected as AEs.  Dietary counseling will be reinforced at intervals throughout the treatment and follow-
up period and all patients will complete a daily food diary for one week prior to their quarterly visit.  All 
blood and urine samples should be collected prior to volanesorsen administration.  Blood sampling at 
Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 
33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51 may be conducted by a home 
healthcare nurse.  Approval for study procedures to be conducted by a home healthcare nurse on other 
outpatient visit days will require prior approval by the Sponsor.  Patients must be fasted prior to drawing 
all blood samples and samples drawn locally should also be sent to the central laboratory for analysis 
whenever possible.  Treatment instructions and training will be provided to the patient where 
applicable. 


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All reasonable attempts should be made to ensure compliance with the visit schedule as outlined in 
Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent visits should 
be calculated based on the time elapsed since Day 1 rather than from the date of the previous visit. 
6.1.4 
Extended Treatment Period 
Patients will have the option of continuing treatment for up to an additional 52 weeks until an expanded 
access program is approved and available in their country. 
During the extended treatment period, patients will report to the study center for clinic visits during 
Weeks 54-104 (see Schedule of Procedures in Appendix A).  Study Drug will be administered once 
weekly unless the patient is on a biweekly treatment schedule for safety reasons (Section 8.1).  
Collection and measurement of vital signs, clinical laboratory parameters (including hematology, serum 
chemistry, and urinalysis), AEs, concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, IM testing, ECGs, and physical examinations will be performed 
according to the Schedule of Procedures in Appendix A.  Adverse events at the injection site should be 
collected as adverse events.  Dietary counseling will be reinforced at intervals throughout the extended 
treatment period.  All blood and urine samples should be collected prior to volanesorsen administration.  
Blood sampling at Weeks 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 
75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 
103 may be conducted by a home healthcare nurse.  Approval for study procedures to be conducted by 
a home healthcare nurse on other outpatient visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples and samples drawn locally should also be 
sent to the central laboratory for analysis whenever possible.  Treatment instructions and training will 
be provided to the patient where applicable. 
6.1.5 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup will have 
more frequent PK sampling over a 24-hour period following the first dose on Study Day 1 in order to 
evaluate the plasma PK parameters of volanesorsen.  Patients in this subgroup will have an additional 
visit to the clinic, or by a home healthcare nurse, on Day 2 to collect a 24-hour post-dose blood draw 
after treatment on Day 1.  The detailed PK sampling schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn for 
the subgroup-specific procedures (e.g., multiple blood draws for PK) without being withdrawn from the 
study.  If a patient withdraws consent from the subgroup procedures, he/she should remain on study 
and continue to follow all the non-subgroup assessments and procedures as outlined in Appendix A. 
6.1.6 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of participating in an 
expanded access program or continuing treatment for up to an additional 52 weeks until an expanded 
access program is approved and available in their country as described in Section 6.1.4.  Patients not 
participating in an expanded access program will enter the 13-week post-treatment evaluation period.  
This 13-week post-treatment evaluation period consists of 7 Study Center visits on Weeks 53, 54, 55, 56, 
57, and 58 (which may be conducted by a home healthcare nurse), and Week 65 as outlined in the 
Schedule of Procedures in Appendix A.  Patients who complete, or terminate early from, the extended 


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treatment period without subsequently participating in an expanded access program will enter a 13-
week post-treatment evaluation period consisting of 7 Study Center visits on Weeks 105, 106, 107, 108, 
109, and 110 (which may be conducted by a home healthcare nurse), and Week 117 as outlined in the 
Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is contained 
in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample 
should be collected in parallel and analyzed locally.  In the event that both the central and local sample 
are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1-week and the result must be reviewed by the Investigator and confirmed to be acceptable 
before treatment can continue.  All platelet count results will be promptly reviewed by the Investigator 
to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the 
dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
Should a patient experience constitutional or flu-like symptoms after Study Drug administration, 
investigators may consider additional laboratory assessments.  For example, plasma and serum samples 
may be drawn for complement (Total C3, C4, C5a and Bb), hsCRP and for cytokine analysis. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures (Appendix 
A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and body temperature.  
Blood pressure and pulse rate will be recorded after the patient has been in a sitting position for at least 
5 minutes.  Semi-supine systolic and diastolic blood pressure should always be measured on the same 
arm (preferentially on the left arm).  Height will be measured at the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma since 
their last visit and the number/duration of the events will be recorded.  Physical exams should also 
include skin examination for presence/resolution of eruptive xanthomas.  If a patient experiences an 
episode of eruptive xanthoma during the study, photos of the area should be taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of the first 
dose of Study Drug (for ISIS 304801-CS16 roll-over patients) and repeated at Week 52.  Images will be 
evaluated by an independent assessor, blinded to the patient’s treatment assignment. 


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6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic valve 
function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of assessment of 
treatment-emergent changes, all echocardiograms will be evaluated on an ongoing basis by an 
independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 5 minutes.  
ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and Week 65.  Patients in 
the Extended Treatment Period will have ECGs performed in triplicate at Week 76 and Week 104. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period (Week 65). 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, Week 26, 
Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient to 
provide diet/alcohol counseling for visits that are conducted by a clinical service.  Patients in the 
Extended Treatment Period will receive diet/alcohol counseling by qualified study personnel at 
clinic visits only. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, telephone 
calls from a dietitian or qualified study personnel to assess as to how each patient is maintaining 
their diet may be conducted randomly during the treatment and post treatment follow-up 
periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 


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6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2 and 3) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior to 
screening and information relating to these events will be collected for independent adjudication. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and either 
be abstinent† or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after their last 
dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the time of 
signing the informed consent until 13 weeks after the subject’s last dose of study treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who has 
experienced menarche, and who does not meet 1 of the following conditions: 
• 
Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical 
cause and FSH levels in the postmenopausal range for the laboratory involved 
• 
6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• 
Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• 
Effective male contraception includes a vasectomy with negative semen analysis at follow-up, or 
the use of condoms together with spermicidal foam/gel/film/ cream/suppository.  Male patients 
must also encourage their female partner to use effective contraception from the time of 
signing the informed consent until 3 months after the patient’s last dose of study treatment.  
Effective contraceptive for the female partner includes: surgical sterilization (e.g., bilateral tubal 
ligation), hormonal contraception, intrauterine contraception/device, or barrier methods 
(female condom*, diaphragm, sponge, cervical cap) together with spermicidal 
foam/gel/film/cream/suppository.  Male patients with partners that are pregnant must use 
condoms to ensure that the fetus is not exposed to the Study Drug. 
For female patients: 
• 
Using 1 or more of the following acceptable methods of contraception:  surgical sterilization 
(e.g., bilateral tubal ligation), hormonal contraception, intrauterine contraception/device, or any 
2 barrier methods (a combination of male or female condom* with diaphragm, sponge, or 
cervical cap) together with spermicidal foam/gel/film/cream/suppository. 
* Note: 
A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 


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† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable 
methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours before 
visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial and that 
serum lipase and/or amylase measures should be done in order to adjudicate the event, based on 
Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 3 x upper limit of 
normal (ULN), imaging, preferably contrast-enhanced computed tomography, should be considered to 
confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7.
STUDY DRUG
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS) or in glass vials.  Volanesorsen 
and its storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2 to 8°C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Study Drug 
ISIS 304801 Prefilled Syringe 
ISIS 304801 Vial 
Strength 
300 mg 
200 mg 
Volume / Formulation 
1.5 mL 
200 mg/mL ISIS 304801 
1.0 mL 
200 mg/mL ISIS 304801 
Dose 
300 mg / 1.5 mL 
150 mg / 0.75 mL 
Route of Administration 
Subcutaneous injection 
Subcutaneous injection 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 


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7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of volanesorsen 
provided by the Sponsor.  The Study Center must return all unused volanesorsen to the Sponsor or 
designee.  All used syringes or vials must be disposed of as per the site’s hazardous waste destruction 
policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 300 mg 
injection once weekly for Weeks 1-52, and patients will continue to receive Study Drug as a single 
300 mg/1.5 mL injection once-weekly for Weeks 53-104 of the study. Patients entering this ISIS 304801-
CS7 study on a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability 
reasons in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or dose 
frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 and 8.6.  
Patients on dose reduction will receive either 300 mg/1.5 mL injections every 2 weeks or 150 mg/0.75 
mL injections once-weekly.  Treatment with a 150 mg dose during the study will use the glass vials 
containing 200 mg/mL of volanesorsen.   
Patients should receive 1 dose per week, unless on a dose reduction of 300 mg every 2 weeks, with 
weeks always defined relative to Study Day 1.  For example, if a patient receives the first dose on a 
Monday, subsequent doses should be given on Mondays, if possible.  If a patient misses an injection, or 
if treatment on the usual day is not possible, the patient can reschedule the injection provided that 2 
doses are administered at least 2 days apart. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring, baseline is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from the final 
visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if used for qualification). 


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In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), the initial 
clinical laboratory results meeting the safety monitoring or stopping criteria presented below must be 
confirmed by performing measurements (ideally in the same laboratory that performed the initial 
measurement) on new specimens.  All new specimen collections should take place as soon as possible 
(ideally within 3 days of the initial collection).  For stopping rules, if the initial laboratory result is 
observed during the Treatment Period, the results from the retest must be available prior to 
administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request confirmation of 
additional lab values. 
Re-treatment Guidance:  Patients with initial laboratory test values that reach a stopping rule must not 
be re-dosed until the re-test results are available.  In general, patients who do not meet the stopping 
rules based upon re-test may continue treatment.  However, the Investigator and the Sponsor Medical 
Monitor (or appropriately qualified designee) should confer as to whether additional close monitoring of 
the patient is appropriate.  Reduction in dose or dose frequency may also be initiated as noted in 
Section 8.7.  If any of the stopping criteria described below (refer to Sections 8.6.1 to 8.6.3) are met, the 
patient will be dose paused or permanently discontinued (as described in the stopping criterion 
concerned) from further treatment with volanesorsen, and evaluated fully as outlined below and in 
consultation with the Sponsor Medical Monitor or appropriately qualified designee, and will be followed 
up in accordance with Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human Services, Food 
and Drug Administration, July 2009.  For a definition of Baseline please refer to guidance in Section 8.5 
above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline value or 3 x 
ULN if the baseline value was > ULN) at any time during the study (Treatment or Post-Treatment Period), 
the initial measurement(s) should be confirmed as described above.  Additional confirmatory 
measurements should also be performed if ALT or AST levels increase to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or the 
greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their liver chemistry 
tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio (INR) and total bilirubin) 
retested at least once-weekly until ALT and AST levels become ≤ 1.2 x ULN or 1.2 x baseline value if the 
baseline value was > ULN. 


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Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST levels > 3 x 
ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN), the following 
evaluations should be performed: 
1.
Obtain a more detailed history of symptoms and prior and concurrent diseases
2.
Obtain further history for concomitant drug use (including nonprescription medications, herbal
and dietary supplement preparations), alcohol use, recreational drug use, and special diets
3.
Obtain a history for exposure to environmental chemical agents and travel
4.
Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV antibody panel)
5.
Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA])
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or MRI 
scans, may be performed at the discretion of the Investigator, in consultation with the Sponsor Medical 
Monitor.  Repetition of the above evaluations should be considered if a patient’s ALT and/or AST levels 
reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3. 
Monitor every 1 week unless otherwise specified.  In addition, platelet function may be evaluated at any 
time during the study by aggregometry, using an approved point-of-care diagnostic device, in some 
patients.  This additional functional testing may be performed at selected study centers. 
Study Drug administration is contingent on the availability of the immediately preceding test result.  An 
interpretable platelet value must be available within 7 days prior to treatment.  Only the study doctor or 
qualified designee can authorize continued Study Drug administration based on an acceptable platelet 
value.  Patients should not administer a dose until they have been contacted by their study doctor or 
designee and told that it is acceptable to dose.  Authorization to dose must be documented in the 
patient’s medical records. 
Due to the 1 to 2-year study duration, it is anticipated that patients may undertake travel including 
vacations, which may impede weekly platelet monitoring.  In some situations, it may be possible to 
arrange for local laboratory testing or use of the home healthcare service at their temporary location.  
The intent is to maintain weekly platelet monitoring and treatment where possible, as well as 
Investigator site contact with the study patients.  However, if the above options are not possible, a 
temporary interruption of study treatment will be planned with a platelet count drawn within 3-5 days 
prior to departure and a prompt blood draw upon the patient’s return which must be reported and 
reviewed by the Investigator prior to the patient resuming treatment. 
Patients on dose pause should be monitored as per the platelet monitoring rules outlined in 
Section 8.8.1 until Study Drug administration is resumed. 
The tests outlined in Table 2 should also be performed as soon as possible.  Additional lab tests will be 
determined by the Sponsor Medical Monitor or designee in consultation with the Investigator.  


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Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
(See also Stopping Rules Section 8.6.3). 
 


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Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower Limit of 
Normal (x2) or < 100,000/mm3 (x1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) of platelet count less than
the lower limit of normal or who have any 1 occurrence of platelets < 100,000/mm3.  Labs only need to
be performed once.  Labs may be collected over multiple visits, if blood requirements are a concern, as
per Investigator discretion.
Note: The following labs may change as additional data is assessed, and sites will be updated regarding
any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-relevant, 
non-major bleeding events (which are defined in Section 8.6.3), for example excess bruising, petechiae, 


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gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the Investigator must notify the 
Sponsor Medical Monitor and additional testing of coagulation parameters activated partial 
thromboplastin time (aPTT), prothrombin time (PT), INR and platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all potential 
causes, including concomitant illness.  Patients that experience persistent constitutional symptoms, 
should be discussed with the Sponsor Medical Monitor or designee to determine whether additional 
monitoring or laboratory tests are required. 
Should a patient experience constitutional or flu-like symptoms after Study Drug administration, 
investigators may consider additional laboratory assessments.  For example, plasma and serum samples 
may be drawn for complement (Total C3, C4, C5a and Bb), hsCRP, and for cytokine analysis. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has a low-
density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with T2DM) on 2 
consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded for the remainder of the 
study and the Investigator will be encouraged to initiate/adjust treatment to lower LDL-C according to 
country-specific guidelines (e.g., initiate statin therapy or increase the statin dose for patients who are 
already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard practice 
guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In addition, 
patients who are not on insulin but use a glucometer should also bring their glucometer and/or 
glucometer log printout to every clinic visit. 
• 
The Investigator or delegate will review the glucometer reading or printout at every clinic visit to 
evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed threshold values 
as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, as well 
as any hypoglycemic episode they may experience. 
• 
The Investigator or delegate will ask patients at every clinic visit if they made changes in their 
insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic episodes at 
each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse events in 
the adverse event CRF. Documented symptomatic hypoglycemia is defined as typical 
hypoglycemia symptoms accompanied by measured plasma glucose ≤ 70 mg/dL (≤ 3.9 
mmol/L). 


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o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires assistance of 
another person to obtain treatment for the event and has a plasma glucose level ≤ 70 mg/dL (≤ 3.9 
mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or buccal or intramuscular 
glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the patient 
when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take immediate 
action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are certain 
classical signs and symptoms, of which patients should be aware as a clue that their blood glucose may 
be low.  Common symptoms include headache, heart pounding, confusion, disorientation, numbness or 
tingling, pale skin, shakiness or tremulousness, increased appetite, anxiousness or nervousness, 
lightheadedness or dizziness, sweating, and weakness.  Coma could occur if blood sugar correction is not 
performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood glucose 
using their meters as soon as possible, before treatment if possible, provided they feel it is safe to do so.  
If there is doubt about safety they should treat the event first, using some sugar, milk, or juice for 
example, then obtain and record a blood glucose value as soon as possible thereafter.  The time and 
nature of treatment should be noted, and especially if any blood glucose result was before or after 
treatment.  It would be helpful for the patient to note if a contributory factor (e.g., missed or reduced 
meals, unaccustomed physical activity) occurred earlier in the day of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be allowed 
during the course of the study, unless specific threshold values are met at Week 13 or later and 
confirmed on subsequent testing (ideally within 1-week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should self-
monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  If a fasting 
pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should check it again on the 
following 2 days.  If all the fasting pre-breakfast values on 3 consecutive days exceed the specific limit, 
the patient should contact the Investigator and an unscheduled central laboratory FPG measurement 
and HbA1c should be performed. 


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The threshold values are defined as: 
• 
FPG > 270 mg/dL (15.0 mmol/L) 
• 
HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 1% from 
baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that no 
reasonable explanation exists for insufficient glucose control and in particular that: 
• 
Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours fast) 
• 
Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• 
Compliance to treatment is appropriate 
• 
Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator should 
consider the following: 
• 
Investigation and treatment of intercurrent disease (to be reported in adverse event 
(AE)/concomitant medication parts of the e-CRF) 
• 
Stress on the absolute need to be compliant to treatment 
• 
Organize a specific interview with a Registered Dietician or other qualified nutrition professional 
and stress on the absolute need to be compliant to diet and lifestyle recommendations 
An FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  If 
none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the Investigator’s 
discretion and according to local guidelines after discussion with the Sponsor Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, treatment with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued treatment 
and the need for any modification to treatment schedule (refer to Section 8.7) will be determined by the 
Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules, baseline is defined as the average of Day 1 pre-dose assessment and 
the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an alternative 
explanation as discussed with the Sponsor Medical Monitor, treatment of a patient with volanesorsen 


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will be stopped permanently; values that are not confirmed due to failure to retest or missing lab values 
will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was > 
ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was > 
ULN), which is confirmed, and the new appearance (i.e., onset coincides with the changes in 
hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, or eosinophilia (> ULN) felt by the Investigator to be potentially related to hepatic 
inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 3 criteria 
below, treatment of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL (26.5 μmol/L) and 
≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault ≤ 40 
mL/min that is confirmed by a 24-hour urine collection 
The possible treatment re-initiation or follow-up schedule for any events meeting either of these criteria 
will be determined by the Investigator in consultation with the Sponsor Medical Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or clinically-
relevant non-major bleeding (defined below; Schulman et al. 2005), treatment of a patient with 
volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting this stopping 
criterion will be determined by the Investigator in consultation with the Sponsor Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 that 
occurs while the patient is treated at 300 mg every 2 weeks or 150 mg once-weekly then treatment of a 
patient with volanesorsen will be stopped permanently.  Platelet count will be monitored as outlined in 
Table 3. 
Administration of steroids is recommended for patients whose platelet count is less than 50,000/mm3.  
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment 
guidelines for immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily 
for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or 


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Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone).  Triglyceride levels will be 
monitored weekly, and AE monitoring will continue, during cortiscosteroid treatment and the laboratory 
alert will be changed from an increase of 2,000 to 500 mg/dL during that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or clinically-
relevant non-major bleeding (defined below; Schulman et al. 2005), treatment of a patient with 
volanesorsen should be suspended temporarily until the platelet count has recovered to 
> 100,000/mm3.  If treatment is reinitiated it should be at a reduced dose frequency of 300 mg every 2 
weeks or 150 mg once-weekly (refer to Section 8.7).  The suitability of the patient for continued 
treatment will be determined by the Investigator in consultation with the Study Medical Monitor and 
will be based on factors such as the original rate of decline in the patient’s platelet count, whether any 
bleeding events were experienced by the patient, and the speed of recovery of platelet count upon 
holding of treatment. 
If after the first treatment re-challenge the platelet count again falls below 75,000/mm3, then treatment 
of the patient with Study Drug will be stopped permanently. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• 
Fatal bleeding, and/or 
• 
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
retroperitoneal, intraarterial or pericardial, or intramuscular with compartment syndrome, 
and/or 
• 
Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 24 hours, or 
leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
 


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Table 3 
Actions in Patients with Low Platelet Count or Drop in Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Study Drug administration is 
contingent on the availability of the 
immediately preceding test result.  An 
interpretable platelet value must be 
available within 7 days prior to 
treatment.  Only the study doctor or 
qualified designee can authorize 
continued Study Drug administration 
based on an acceptable platelet value.  
Patients should not administer a dose 
until they have been contacted by their 
study doctor or designee and told that 
it is acceptable to dose.  Authorization 
to dose must be documented in the 
patient’s medical records. 
Monitor every 1 week unless otherwise 
specified 
In addition, platelet function may be 
evaluated during the study by 
aggregometry, using an approved 
point-of-care diagnostic device, in some 
patients.  This additional functional testing 
may be performed at selected study 
centers. 
Patients on dose pause should be 
monitored as per the platelet monitoring 
rules outlined in Section 8.8.1 until Study 
Drug administration is resumed. 
Obtain additional lab tests (Table 2) if 
2 occurrences consecutive or non-
consecutive) of platelet count 140K - 
> 100K/mm3 or 1 occurrence of platelet
count ≤ 100K/mm3.  Labs only need to be
performed once.  Labs may be collected
over multiple visits, if blood requirements
are a concern, as per Investigator
discretion.
> 100K/mm3
Once-weekly 300 mg Study Drug 
administration 
100K/mm3 - >75K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks or 150 mg 
once-weekly 
75K/mm3 - >50K/mm3 
• If occurs while on dose of 300 mg
every 2 weeks or 150 mg
once-weekly then permanently
discontinue Study Drug, otherwise
dose pause. If dose pause is
≥ 3 months then patient must
discontinue treatment and enter the
follow up period.
• When platelet count returns to
> 100K/mm3 restart treatment at
dose frequency of 300 mg every 2
weeks or 150 mg once-weekly in
consultation with the Sponsor
Medical Monitor
•
Monitor every 2-3 days until
2 successive values are > 75K/mm3 
then monitor every 1 week
•
Consider discontinuation of
antiplatelet agents/NSAIDS/
anticoagulant medication


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Platelet Count on Rx 
Drug Dose 
Monitoring 
≤ 50K/mm3 
Permanently discontinue Study Drug 
and the patient will enter the follow up 
period 
• Monitor daily until 2 successive values
show improvement then monitor every
2-3 days until 2 successive values are
> 75K/mm3 then monitor every 1 week
• Patient should be evaluated by a
hematologist to provide diagnostic and
therapeutic management
• Steroids recommended*.  It is strongly
recommended that, unless the patient
has a medical contraindication to
receiving glucocorticoids, the patient
receives glucocorticoid therapy to
reverse the platelet decline.
• Monitor triglyceride levels weekly and
continue AE monitoring during steroid
therapy
• Discontinue antiplatelet agents/
NSAIDS/ anticoagulant medication while
platelet count is < 50K/mm3 if possible
*
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for
immune thrombocytopenia (Provan et al. 2010) recommend dexamethasone 40 mg daily for 4 days every
2-4 weeks for 1-4 cycles; prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or methylprednisolone
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methylprednisolone)
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 3 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose to 150 mg 
once-weekly or the dose frequency to 300 mg every 2 weeks will be allowed for safety and tolerability.  
Any proposed adjustment to treatment schedule must be discussed with, and approved by, the Study 
Medical Monitor prior to initiation.  Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs, and the Study Medical Monitor is informed. If a patient 
is dose paused for ≥ 3 months, he or she is considered to have discontinued treatment and should enter 
the 13-week post-treatment follow-up period. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
•
The patient becomes pregnant.  Report the pregnancy according to instructions in Section 9.5.4.
•
The patient withdraws consent.
•
The patient experiences an AE that necessitates permanent discontinuation of study treatment.
•
The patient develops laboratory test abnormalities that meet any of the stopping rules listed in
Section 8.6.
•
The patient is dose paused for ≥ 3 months.


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The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the platelet 
monitoring rules shown in in Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  
Following this period, if the platelet count is stable (at least 3 consecutive values that are stable as 
determined by the Sponsor Medical Monitor and > 100,000/mm3), the next platelet count should be 
taken within at least 6 weeks so that patients are monitored for at least 12 weeks after discontinuing 
Study Drug.  Any patient who discontinues treatment after Week 44 should also be strongly encouraged 
to attend a final follow-up visit (Week 65 visit assessments) approximately 13 weeks after their last dose 
of Study Drug. 
A patient who discontinues early from treatment with stable platelet counts above the LLN at the time 
of treatment discontinuation will have platelet counts drawn every 2 weeks after discontinuing Study 
Drug for the first 6 weeks after the last dose of Study Drug.  A subsequent platelet count should then be 
taken after an additional 6 weeks so that patients are monitored for at least 12 weeks after 
discontinuing Study Drug. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and ideally 
within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up Period 
should be encouraged to follow the platelet monitoring rules shown in Table 3 in Section 8.6.3 for the 
first 6 weeks after discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and > 
100,000/mm3), the next platelet count should be taken within at least 6 weeks so that patients are 
monitored for at least 12 weeks after discontinuing Study Drug.  Patients should also be encouraged to 
undergo a final follow-up visit (Week 65 or Week 117 if terminating from the Extended Treatment 
Follow-Up Period), see Appendix A) prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange for the 
patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
•
Withdrawal of consent
•
The patient is unwilling or unable to comply with the protocol
Other reasons for withdrawal of patients from the study might include: 
•
At the discretion of the Investigator for medical reasons
•
At the discretion of the Investigator or Sponsor for noncompliance


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• 
Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to the 
date of withdrawal.  All information, including the reason for withdrawal from study, must be recorded 
in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further treatment 
and study observation immediately upon the date of request.  These patients should be encouraged to 
complete the ET study procedures and observations at the time of withdrawal (see Section 8.8 and 
Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent, every effort should be made to 
complete the early termination study procedures and observations at the time of withdrawal (see 
Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s CRF.  
AEs related to administration of these therapies or procedures must also be documented on the 
appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-counter 
medications, herbal medications and vitamin supplements) administered between signing informed 
consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be recorded 
in the patient’s source documents and CRF.  Patients taking over the counter (OTC) omega-3 fatty acids 
should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the disallowed 
concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 fatty 
acids [including over-the-counter preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, or 
systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of existing oral 
anti-diabetic medication, oral contraceptives, hormone replacement therapy, anticoagulants, or drugs 
or dietary supplements with potential lipid-altering effects should not be adjusted.  Study patients are 
prohibited from receiving other experimental agents during the study.  This includes marketed agents at 
experimental dosages that are being tested for the treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new medication, 
including non-prescription or herbal compounds or any other non-drug therapy. 


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8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) or 
diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between signing of 
informed consent and Week 65 (or Week 117 if patient enters the extended treatment period) visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The Study 
Center staff is required to document the receipt, dispensing, and return/destruction of volanesorsen.  
Patients that are self-administering volanesorsen at home must record treatment in a dosing diary that 
will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with the 
Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of serious 
adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs) per the 
International Conference on Harmonization (ICH) guidelines E2A and ICH E6 (R2).  Country-specific 
regulatory requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any SAE 
according to applicable regulations.  The Independent DSMB will be notified of any SAE as specified in 
the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate the 
available information and perform an independent assessment of relatedness.  While the Sponsor may 
upgrade an Investigator’s decision it is not permissible to downgrade the Investigator’s opinion for the 
purposes of determining whether the SAE meets the definition of a SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an individual basis 
in an expedited manner because they are anticipated to occur in the study population independent of 
volanesorsen exposure.  The Investigator still has the responsibility to report all SAEs to the Sponsor as 
described in Sections 9.4.1 to 9.4.3.5. 


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Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and the 
Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The Sponsor 
and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate of the event 
compared to the rate expected in a non-volanesorsen exposed population.  If the aggregate analysis 
indicates that an event is occurring significantly more frequently or at a greater severity than expected, 
then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether there is a 
reasonable possibility that the drug caused the event.  If the event is considered by the Sponsor or 
designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the study or use of 
investigational drug product, whether or not the AE is considered related to the investigational drug 
product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or Sponsor, 
meets any of the following criteria: 
• 
Results in death 
• 
Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not include 
an AE or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
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• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Hospitalization is defined as an admission of greater than 24 hours to a medical facility and does 
not always qualify as an AE 
• 
Results in a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Results in congenital anomaly or birth defect in the offspring of the patient (whether the patient 
is male or female) 
• 
Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the study 
(i.e., before informed consent) should be recorded as Medical History and not recorded as AEs unless 
the pre-existing condition worsened.  The Investigator should always group signs and symptoms into a 
single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to volanesorsen) should be reported to the Sponsor or designee within 24 hours of the 
Study Center’s first knowledge of the event.  The collection of SAEs will begin after the patient signs the 
informed consent form and stop at the end of the patient’s follow-up period which is defined as the 
Week 65 visit (or Week 117 if patient enters the extended treatment period).  When the Investigator is 
reporting by telephone, it is important to speak to someone in person versus leaving a message.  An 
Initial Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse Event Forms 
as soon as additional information becomes available.  All SAEs will be followed until resolution.  SAEs 
that remain ongoing past the patient’s last protocol-specified follow-up visit will be evaluated by the 
Investigator and Sponsor.  If the Investigator and Sponsor agree the patient’s condition is unlikely to 
resolve, the Investigator and Sponsor will determine the follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form and will 
stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit (or Week 117 if 
patient enters the extended treatment period).  The Investigator will monitor each patient closely and 
record all observed or volunteered AEs on the Adverse Event Case Report Form. 


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9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case Report 
Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• 
Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• 
Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event and 
volanesorsen administration 
• 
Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is unlikely (For 
reporting purposes, Unlikely/Remote will be grouped together with Not Related) 
• 
Not Related:  The event can be readily explained by the patient’s underlying medical condition, 
concomitant therapy, or other causes, and therefore, the Investigator believes no relationship 
exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE not listed in Appendix D 
will be graded as follows: 
• 
Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual daily 
activities 
• 
Moderate:  The event causes the patient more discomfort and interrupts the patient’s usual 
daily activities 
• 
Severe:  The event is incapacitating and causes considerable interference with the patient’s 
usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in Section 
9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• 
None:  No changes were made to volanesorsen administration and dose 
• 
Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• 
Temporarily Interrupted, restarted – same dose:  Treatment was temporarily interrupted or 
delayed due to the AE and restarted at the same dose 


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• 
Reduced schedule:  Treatment frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the Adverse 
Event Case Report Form (treatment should also be recorded on the concomitant treatment or ancillary 
procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• 
AE Persists:  Patient terminates from the trial and the AE continues 
• 
Recovered:  Patient recovered completely from the AE 
• 
Became Serious:  The event became serious (the date that the event became serious should be 
recorded as the Resolution Date of that AE and the Onset Date of the corresponding SAE) 
• 
Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• 
Ongoing:  SAE continuing 
• 
Persists (as non-serious AE):  Patient has not fully recovered but the event no longer meets 
serious criteria and should be captured as an AE on the non-serious AE eCRF (the SAE resolution 
date should be entered as the date of onset of that AE) 
• 
Recovered:  Patient recovered completely from the SAE (the date of recovery should be entered 
as the SAE resolution date) 
• 
Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event (MACE) 
will be adjudicated by a blinded, independent committee as outlined in the MACE Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute pancreatitis will 
be adjudicated by a blinded, independent committee according to the Atlanta classification of acute 
pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis Adjudication Charter.  In addition, 
data for prior episodes of acute pancreatitis or suspected pancreatitis will be collected by review of each 
patient’s medical chart and these events will also be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, constitute 
or be associated with an AE.  Examples of these include abnormal laboratory results that are associated 
with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, tetany due to 
hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the underlying 


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diagnosis should be listed in preference to abnormal laboratory values as AEs.  Clinically-significant 
abnormalities will be monitored by the Investigator until the parameter returns to its baseline value or 
until agreement is reached between the Investigator and Sponsor Medical Monitor.  Laboratory 
abnormalities deemed not clinically-significant (NCS) by the Investigator should not be reported as AEs.  
Similarly, laboratory abnormalities reported as AEs by the Investigator should not be deemed NCS on 
the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed clinical 
laboratory reports will serve as source documents and should include the Investigator’s assessment of 
clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered an SAE, 
even if the patient is hospitalized; the Study Center must document all of the following: 
• 
The prescheduled or elective procedure or routinely scheduled treatment was scheduled (or 
was on a waiting list to be scheduled) prior to obtaining the patient’s consent to participate in 
the study 
• 
The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the Investigator 
between the patient’s consent to participate in the study and the timing of the procedure or 
treatment 
• 
The prescheduled or elective procedure or routinely scheduled treatment is the sole reason for 
the intervention or hospital admission 
9.5.3 
Treatment Errors 
Volanesorsen treatment errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
Treatment details should be captured on the Treatment Case Report Form.  If the patient takes a dose of 
volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the symptom(s) 
should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to Investigator’s 
section of the Investigator’s Brochure and contact the Sponsor or designee within 24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes that he 
has made someone pregnant during the study, then the Study Center staff must be informed 
immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or designee within 24 


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hours of first learning of the occurrence of pregnancy.  Follow-up information including delivery or 
termination is reported on Follow-up Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a pregnancy 
test will be performed.  The patient with a confirmed pregnancy will be immediately withdrawn from 
treatment with volanesorsen.  However, the patient will be encouraged to complete the post-treatment 
follow-up portion of the study to the extent that study procedures do not interfere with the pregnancy.  
Regardless of continued study participation, the study physician will assist the patient in getting 
obstetrical care and the progress of the pregnancy will be followed until the outcome of the pregnancy 
is known (i.e., delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the 
birth of a child, the Study Center and Sponsor may require access to the mother and infant’s medical 
records for an additional 8 weeks after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed until the 
outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous abortion).  If the 
pregnancy results in the birth of a child, the Study Center and Sponsor may request access to the 
mother and infant’s medical records for an additional 8 weeks after birth.  Follow-up will be performed 
to the extent permitted by applicable regulations and privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the average of 
Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 analysis time point 
is at the end of Month 6 are defined as the average of Week 25 (Day 169) and Week 26 (Day 176) fasting 
assessments, and the values at the Month 12 analysis time point are defined as the average of Week 50 
(Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during the treatment period 
• 
Percent change and change from baseline in other fasting lipid measurements including total 
cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 


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10.1.2 
Safety Endpoints 
• 
Adverse events including adjudicated events of pancreatitis and MACE 
• 
Vital signs and weight 
• 
Physical examinations  
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active Study Drug 
and have a baseline TG assessment.  The FAS represents the practically-feasible intent-to-treat (ITT) 
population as delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of volanesorsen 
and with no significant protocol deviations that would be expected to affect efficacy and PD 
assessments.  The detailed criteria will be specified and finalized prior to the final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have at least 1 
post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  Group 1 (ISIS 
304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the baseline in this open-label 
study, which is defined as the average of Day 1 pre-dose assessment and the last measurement prior to 
Day 1 (e.g., qualification assessments or assessments from final visit of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies if used for qualification).  For Group 3 patients, the baseline for fasting 
lipid measurements is defined as the average of Day 1 pre-dose assessment and the last measurement 
prior to Day 1 in this open-label study. 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or ISIS 
304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study baseline.  For 
patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study and Group 3 patients, 
baseline will be the last non-missing assessment prior to the first dose of Study Drug. 


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10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label study or 
after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are locked and unblinded.  
Both safety and efficacy information from this open-label study may be summarized during this interim 
analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be provided in the 
patient data listings.  Patient data listings will be presented for all patients enrolled into the study.  
Descriptive summary statistics including n, mean, median, standard deviation, standard error, 
interquartile range (25th percentile, 75th percentile), and range (minimum, maximum) for continuous 
variables, and counts and percentages for categorical variables will be used to summarize most data by 
treatment group of the index studies for patients on active in the ISIS 304801-CS6 or ISIS 304801-CS16 
index studies, and pooled treatment naive group which including patients on placebo in index studies 
and Group 3 patients.  Where appropriate, p-values will be reported.  All statistical tests will be 
conducted using 2-sided tests with 5% Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will be 
assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK endpoints will be 
assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by treatment 
group and overall.  The patient disposition will be summarized by treatment group and overall.  All 
patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group and 
overall. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA preferred 
term, and treatment group of the index studies.  Narratives of treatment-emergent deaths, serious and 
significant AEs, including early withdrawals due to AEs, will also be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to Study 
Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term and 
severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) with 
differential, coagulation panel, IM, complement etc., will be summarized by study visits by treatment 
group. 


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These safety variables will also be presented as change and percent change from baseline over time 
after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will be 
summarized by treatment group.  Response rate of patients with fasting plasma TG < 750 mg/dL or 
achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and Month 12 will be 
summarized.  Response analysis will also be conducted using a range of fasting plasma TG thresholds for 
determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be summarized 
by treatment group for other fasting lipid measures including non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, 
and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association between 
changes in lipid parameters and total amount of drug received will be examined, as appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event rate, 
quality of life assessments, and comparison of other symptoms including eruptive xanthomas and 
lipemia retinalis will be summarized by treatment group. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be summarized 
using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be carried out 
on each individual patient data set using data collected in the open-label study from the intensive PK 
subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., steady-state PK), 
depending on their earlier treatment in the index studies (Group 1 and 2 patients).  On Week 1 Day 1 of 
the open-label study, patients who received placebo in the index study (and all patients in Group 3) will 
receive the first treatment of volanesorsen (single-dose PK), while patients who received volanesorsen 
in the index studies had been on volanesorsen treatment for 12 months (ISIS 304801-CS6) or 6 months 
(ISIS 304801-CS16), thus the PK data collected from these patients reflect steady-state PK.  The 
maximum observed drug concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained 
directly from the concentration-time data.  Area under the plasma concentration-time curve from time 
zero to 24 hours (AUC0-24h) will be calculated using the linear trapezoidal rule.  Apparent systemic 
(plasma) clearance after SC administration (CL0-24h /F) will be calculated from  
CL0-24h/F = Actual Dose/AUC0-24h.  Mean residence time (MRT) from time zero to 24 hours after the SC 
administration will be calculated from the equation,  
MRT0-24h = AUMC0-24h/AUC0-24h, where AUMC0-24h is the area under the moment plasma concentration-


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time curve from time zero to 24 hours after the SC administration.  Other PK parameters, as 
appropriate, may be determined or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM status.  
Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and results will 
be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not evaluable, 
and when applicable, titer of anti-volanesorsen antibodies) before, during, and after treatment with 
Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be listed by their prior 
treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subject ADA 
status (positive/negative or not evaluable) for all evaluable patients, along with the study day associated 
with the first positive IM status emerged (Tfirst, i.e., onset of ADA development), the last positive IM 
status observed (Tlast), the last ADA sample collection day, and subject - peak titer if applicable, will be 
listed by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and 
study day.  Subjects with positive anti-volanesorsen antibody status may be further classified (when 
applicable) as being either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, positive, and 
unknown status by treatment group.  Furthermore, onset and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy (e.g., % 
change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK (e.g., Ctrough) 
measures will be evaluated using graphical analysis and statistical analysis.  These analyses will be either 
conducted and included in the study report, or data pooled and analyzed from all available Phase 2 and 
3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential patient 
population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written informed 
consent from the patient after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study and before any protocol-specific qualification procedures or any Study 
Drug are administered.  The patient must be given sufficient time to consider whether to participate in 
the study. 


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The acquisition of informed consent and the patient’s agreement or refusal to notify his/her primary 
care physician should be documented in the patient’s medical records and the informed consent form 
should be signed and personally dated by the patient and by the person who conducted the informed 
consent discussion (not necessarily an Investigator).  The original signed informed consent form should 
be retained in the Study Master File and in any other locations required by institutional policy, and a 
copy of the signed consent form should be provided to the patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 2002 the 
applicable regulations and guidelines of current Good Clinical Practice (GCP) as well as the demands of 
national drug and data protection laws and other applicable regulatory requirements will be strictly 
followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and any 
proposed advertising material must be submitted to the IEC/IRB for written approval.  A copy of the 
written approval of the protocol and informed consent form must be received by the Sponsor before 
recruitment of patients into the study and shipment of volanesorsen.  A copy of the written approval of 
any other items/materials that must be approved by the Study Center or IEC/IRB must also be received 
by the Sponsor before recruitment of patients into the study and shipment of Study Drug.  The 
Investigator’s Brochure must be submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The Investigator 
should notify the IEC/IRB of deviations from the protocol in accordance with ICH E6 (R2) Section 4.5.2.  
The Investigator should also notify the IEC/IRB of serious adverse events occurring at the Study Center 
and other adverse event reports received from the Sponsor, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout the 
duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the IEC/IRB 
continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report forms 
(CRF) or other documents submitted to the Sponsor, patients should be identified by unique initials and 
a patient study number only.  Documents that are not for submission to the Sponsor (e.g., signed 
informed consent forms) should be kept in strict confidence by the Investigator. 
In compliance with Federal and local regulations/ICH E6 (R2) Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for verification 
of study-related procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  The Investigator 
is obligated to inform and obtain the consent of the patient to permit named representatives to have 
access to his/her study-related records without violating the confidentiality of the patient. 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement from the 
Investigator must be obtained for all protocol amendments and amendments to the informed consent 
document.  The regulatory authority and IEC/IRB must be informed of all amendments and give approval 
for any amendments likely to affect the safety of the patients or the conduct of the trial.  The 
Investigator must send a copy of the approval letter from the IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  The 
Investigator reserves the right to terminate their participation in the study, according to the terms of the 
site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the trial’s completion or 
early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application will be used 
for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has delegated 
trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities Form. 
Source documents are original documents, data, and records from which the patient’s CRF data are 
obtained.  These include but are not limited to hospital records, clinical and office charts, laboratory and 
pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs may not be used as source 
documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with Section 8 of 
ICH E6 (R2), suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Elements should include: 
• 
Patient files containing completed CRFs, informed consents, and supporting copies of source 
documentation 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, copies of pre-
study documentation and all correspondence to and from the IEC/IRB and the Sponsor 
• 
If volanesorsen supplies are maintained at the Study Center, proof of receipt, volanesorsen 
Accountability Record, Return of volanesorsen for Destruction, final study volanesorsen 
reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and be 
readily available. 


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No study document should be destroyed without prior written agreement between the Sponsor or and 
the Investigator.  Should the Investigator wish to assign the study records to another party or move 
them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the trial (e.g., CRFs and other pertinent data) provided that patient confidentiality is 
respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence 
to local regulations on the conduct of clinical research.  The monitor should have access to patient 
medical records and other study-related records needed to verify the entries on the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH E6 (R2) and the Sponsor’s audit plans, this study may be selected for audit by 
representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of Study Center 
facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-related records will occur 
to evaluate the trial conduct and compliance with the protocol, ICH E6 (R2), and applicable regulatory 
requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on patient 
data received by the Sponsor.  During this review, patient data will be checked for consistency, 
omissions, and any apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data management review process, 
data queries and/or Study Center notifications will be sent to the Study Center for completion and 
return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures will 
indicate that the principal Investigator inspected or reviewed the data on the CRF, the data queries, and 
the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications should be 
recorded in English if possible, unless it is a combination drug, then record the trade name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow applicable local 
compensation laws.  Patients will be treated and/or compensated for any study-related illness/injury in 


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accordance with the information provided in the Compensation for Injury section of the Informed 
Consent document. 
 
 


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13. 
REFERENCES 
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to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine society 
clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of particle 
size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular risk 
factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and interaction 
with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J Med 
371; 23 Dec 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Gaudet D, Baass A, Tremblay K, et al. Natural History (up to 15 years) of Platelet Count in 84 Patients with Familial 
Hyperchylomicronemia Due to Lipoprotein Lipase Deficiency. Journal of Clinical Lipidology 2017; 11(3): 797-798. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
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Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
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Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
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Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic 
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Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
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Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and 
apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
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Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
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ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
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Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
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Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and apolipoprotein 
C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica Chimia Acta 2011; 
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severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe hypertriglyceridemia. 
J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
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14.
APPENDICES
Appendix A 
Schedule of Procedures 


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Appendix A 
Schedule of Procedures 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-8 to 
 -2 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 44
9 
Visit Window+/- Days 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Physical Examination 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Blood Draw (Fasting)d 
Chemistry Panel 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC with Differentialc 
X 
X 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
X 
Serum Lipid Panel 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Blood viscositye 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Platelet aggregatione 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Coagulation (aPTT, PT, INR) 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
HbA1c 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Sedimentation Rate 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Troponin I 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Platelet Bound Autoantibodiese 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK - Volanesorsen 
 
 
Xn 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
 
21 November 2018 
 
82 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-8 to 
 -2 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 44
9 
Visit Window+/- Days 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
FSH (women only, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testf 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Appendix A 
Schedule of Procedures Continued 
Study Period 
Screen/ 
Run Ina Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-8 to 
 -2 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
 
 
 
Wk 
25 
Wk 
26 
 
 
 
 
 
 
 
Wk 
50 
Wk 52 
or ET 
 
 
 
Study Day 
-56 to 
-15 
-14 to 
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Blood Draw 
(Fasting)d 
Archive blood sample for potential 
gene sequencing related to 
hypertriglyceridemia (Group 3; 
Group 2 if not available from index 
study)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Serum & Plasma 
Samplesg 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Urinalysisd 
X 
X 
Xo 
 
X 
 
X 
 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
Xo 
Fundus Photographyh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Genetic testing for FCS diagnosis (if 
not available in medical history)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Once-weekly Study Drug:  SC Injection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
 
21 November 2018 
 
83 
Study Period 
Screen/ 
Run Ina Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-8 to 
 -2 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
 
 
 
Wk 
25 
Wk 
26 
 
 
 
 
 
 
 
Wk 
50 
Wk 52 
or ET 
 
 
 
Study Day 
-56 to 
-15 
-14 to 
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Quality of Life Assessment(s) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Food/Drink Diary (quarterly)j 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Diet/Alcohol Counselingk 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Screening and Qualification (Group 3) procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Patient charts will be reviewed in order to collect data for events of acute pancreatitis or suspected pancreatitis in the patient’s medical history.  Chart review may be 
conducted at any time during the study.  These events will be adjudicated in the same manner as for events of pancreatitis during the study 
c 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally.  In the 
event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 1 week and 
the result must be reviewed by the Investigator and confirmed to be acceptable before treatment can continue.  All platelet count results will be promptly reviewed by 
the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3.  Any case of a 
platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
 
21 November 2018 
 
84 
Appendix A 
Schedule of Procedures Continued 
Legend Text Continued 
d 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
e 
May be done.  Blood viscosity and platelet aggregation in volanesorsen-treatment naïve patients only 
f 
Females of childbearing potential only 
g 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of 
volanesorsen 
h 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 [ISIS 304801-CS16 roll-over patients] and 
Group 3) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
i 
Genetic testing can be conducted for study qualification (Group 2 [ISIS 304801-CS16 roll-over patients] and Group 3); genetic testing will only be conducted if 
allowed in the geographic region and only after the patient has given specific written informed consent for genetic testing.  A blood sample for potential gene 
sequencing may be collected at timepoints other than Screening or Qualification Visits. 
j 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
k 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
l 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
m 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
n 
Full or abbreviated PK profile (see Appendix C) 
o 
Expanded urinalysis (see Appendix B) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
 
21 November 2018 
 
85 
Appendix A 
Schedule of Procedures – Extended Treatment Period 
Study Period 
Treatment Period 
Post-Treatment 
Follow-up 
Study Week 
Wk 54 
& 56 
Wk 
58 
Wk 60 
& 62 
Mo 15 
Wk 64 
Wk 66 
& 68 
Wk 
70 
Wk 72 
& 74 
Mo 18 
Wk 76 
Wk 78 
& 80 
Wk 
82 
Wk 84, 
86, & 88 
Mo 21 
Wk 90 
Wk 92 
& 94 
Wk 
96 
Wk 
98, 
100 & 
102 
Mo 24 
Wk 
104 
Wk 
106 
& 
108 
Wk 
110 
Mo 27 
Wk 
117 
Study Day 
372 & 
386 
400 414 & 
428  
442 
456 & 
470 
484 498 & 
512 
526 
540 & 
554 
56
8  
582, 596 
& 610 
624 
638 & 
652 
666 
680, 
694 & 
708 
722 
736  
& 
750 
764 
813 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Outpatient Visit 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
X 
Vital Signs (+ body weight) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis(including P/C ratio) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood Draw (Fasting)b 
Chemistry Panel 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CBC with Differentiala 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
X 
Serum Lipid Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Troponin I 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 304801c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-ISIS 304801 Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Serum Pregnancy Testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Platelet Function g 
                                                                                                       X 
May be assessed at various timepoints, visits do not have specified windows to allow flexibility of scheduling. 
Once-weekly Study Drug: SC 
Injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diet/Alcohol Counselinge 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
 
21 November 2018 
 
86 
Study Period 
Treatment Period 
Post-Treatment 
Follow-up 
Study Week 
Wk 54 
& 56 
Wk 
58 
Wk 60 
& 62 
Mo 15 
Wk 64 
Wk 66 
& 68 
Wk 
70 
Wk 72 
& 74 
Mo 18 
Wk 76 
Wk 78 
& 80 
Wk 
82 
Wk 84, 
86, & 88 
Mo 21 
Wk 90 
Wk 92 
& 94 
Wk 
96 
Wk 
98, 
100 & 
102 
Mo 24 
Wk 
104 
Wk 
106 
& 
108 
Wk 
110 
Mo 27 
Wk 
117 
Study Day 
372 & 
386 
400 414 & 
428  
442 
456 & 
470 
484 498 & 
512 
526 
540 & 
554 
56
8  
582, 596 
& 610 
624 
638 & 
652 
666 
680, 
694 & 
708 
722 
736  
& 
750 
764 
813 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
 
21 November 2018 
 
87 
Appendix A 
Schedule of Procedures – Extended Treatment Period Continued 
Legend Text 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1 week and the result must be reviewed by the Investigator and confirmed to be acceptable before treatment can continue.  All platelet count results will 
be promptly reviewed by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule 
of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor.  
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration 
c 
Abbreviated PK collection (see Appendix C) 
d 
Females of childbearing potential only 
e 
To reinforce compliance to the diet and alcohol restrictions 
f 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
g     May be done 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
88 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
89 
Appendix B 
List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be performed 
on stored samples to better characterize the profile of volanesorsen or other similar oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Screening Tests (Group 3) 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (women only) 
• 
Serum βhCG (women 
only) 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% and 
absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
Troponin I2 
• 
CK-MB2 
• 
Platelet Bound 
Autoantibodies3 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
• 
Blood viscosity3 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination4 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
Platelet Function 
• 
Platelet aggregation3 
• 
Platelet Function5 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
3 
May be done 
4 
Will be performed on abnormal findings unless otherwise specified 
5 
May be done using a point-of-care device on site 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
90 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
91 
Appendix C 
Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected prior to 
treatment, and at various times throughout the treatment and post-treatment follow-up period as 
noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (Extended Treatment Period) 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Study Day 
D526 
D722 
D813 
Visit Window 
+/- Days 
2 
2 
7 
Time Point 
Pre-dose,  
Pre-dose 
Anytime 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
92 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
93 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are based 
upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
94 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol 
21 November 2018 
 
95 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 
 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 8 - France – 10 April 2017 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 30480 l -CS7 
Protocol - France 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 8 
IO April 2017 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 8 - France - 10 April 2017 
Protocol History: 
Original Protocol: 
Protocol Amendment 1: 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Protocol Amendment 5: 
Protocol Amendment 6: 
Protocol Amendment 7: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
A 
28 August 2015 
2 February 2016 
22 April 2016 
9 May 2016 
6 June 2016 
19 August 2016 
16 September 2016 
3 February 2017 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 8 - France 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone:
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
10 April 2017 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 8 - France 
Date:  
 
10 April 2017 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 10 April 2017, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT...................................................................................................... 9 
PROTOCOL SYNOPSIS ........................................................................................................... 19 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 25 
STUDY GLOSSARY .................................................................................................................. 26 
1. 
OBJECTIVES ................................................................................................................. 28 
2. 
BACKGROUND AND RATIONALE .......................................................................... 28 
2.1 
Overview of Disease ......................................................................................................28 
2.2 
Therapeutic Rationale ....................................................................................................29 
2.3 
Volanesorsen ..................................................................................................................30 
2.3.1 
Mechanism of Action .............................................................................................30 
2.3.2 
Chemistry ...............................................................................................................31 
2.3.3 
Preclinical Experience ............................................................................................32 
2.3.4 
Clinical Experience ................................................................................................33 
2.4 
Rationale for Dose and Schedule of Administration .....................................................34 
3. 
EXPERIMENTAL PLAN .............................................................................................. 35 
3.1 
Study Design ..................................................................................................................35 
3.2 
Number of Study Centers ..............................................................................................35 
3.3 
Number of Patients ........................................................................................................35 
3.4 
Overall Study Duration and Follow-up .........................................................................35 
3.4.1 
Qualification ...........................................................................................................35 
3.4.2 
Treatment ................................................................................................................35 
3.4.3 
Post-Treatment .......................................................................................................35 
3.5 
End-of-Study ..................................................................................................................35 
3.6 
Data and Safety Monitoring Board ................................................................................35 
4. 
PATIENT ENROLLMENT ........................................................................................... 36 
4.1 
Qualification ..................................................................................................................36 
4.2 
Enrollment .....................................................................................................................36 
5. 
PATIENT ELIGIBILITY .............................................................................................. 36 
5.1 
Inclusion Criteria ...........................................................................................................36 
5.2 
Exclusion Criteria ..........................................................................................................37 
6. 
STUDY PROCEDURES ................................................................................................ 40 
6.1 
Study Schedule ..............................................................................................................40 
6.1.1 
Qualification ...........................................................................................................40 
6.1.2 
Treatment Period ....................................................................................................40 
6.1.3 
Pharmacokinetic (PK) Subgroup ............................................................................41 
6.1.4 
Post-Treatment Period ............................................................................................41 
6.2 
Additional Study Assessments .......................................................................................41 
6.2.1 
Laboratory Assessments .........................................................................................41 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
6 
6.2.2 
Physical Exams and Vital Signs .............................................................................41 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................42 
6.2.2.2 
Lipemia Retinalis .............................................................................................42 
6.2.3 
Echocardiography ...................................................................................................42 
6.2.4 
ECG ........................................................................................................................42 
6.2.5 
MRI ........................................................................................................................42 
6.2.6 
Quality of Life Assessments ...................................................................................42 
6.2.7 
Disease Symptom Diary .........................................................................................42 
6.2.8 
Diet Monitoring ......................................................................................................42 
6.2.9 
Family History ........................................................................................................43 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) ..43 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................43 
6.3.1 
Contraception Requirements ..................................................................................43 
6.3.2 
Other Requirements ................................................................................................44 
7. 
STUDY DRUG ................................................................................................................ 44 
7.1 
Volanesorsen Description ..............................................................................................44 
7.2 
Packaging and Labeling .................................................................................................45 
7.3 
Study Drug Accountability ............................................................................................45 
8. 
TREATMENT OF PATIENTS ..................................................................................... 45 
8.1 
Volanesorsen Administration ........................................................................................45 
8.2 
Other Protocol-Required Drugs .....................................................................................45 
8.3 
Other Protocol-Required Treatment Procedures ............................................................45 
8.4 
Treatment Precautions ...................................................................................................46 
8.5 
Safety Monitoring Rules ................................................................................................46 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................46 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................47 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................49 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................49 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................49 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........49 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................50 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................50 
8.5.9 
Acute Pancreatitis ...................................................................................................51 
8.6 
Stopping Rules ...............................................................................................................51 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................52 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................52 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................52 
8.7 
Adjustment of Dose Frequency .....................................................................................55 
8.8 
Discontinuation of Study Treatment ..............................................................................55 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................55 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
7 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .56 
8.9 
Withdrawal of Patients from the Study ..........................................................................56 
8.10 
Concomitant Therapy and Procedures ...........................................................................57 
8.10.1 
Concomitant Therapy .............................................................................................57 
8.10.2 
Concomitant Procedures .........................................................................................57 
8.11 
Treatment Compliance ...................................................................................................57 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 58 
9.1 
Sponsor Review of Safety Information .........................................................................58 
9.2 
Regulatory Requirements ..............................................................................................58 
9.3 
Definitions .....................................................................................................................59 
9.3.1 
Adverse Event ........................................................................................................59 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................59 
9.3.3 
Serious Adverse Event (SAE) ................................................................................59 
9.4 
Monitoring and Recording Adverse Events ...................................................................60 
9.4.1 
Serious Adverse Events ..........................................................................................60 
9.4.2 
Non-Serious Adverse Events ..................................................................................60 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................60 
9.4.3.1 
Relationship to the Study Drug ........................................................................60 
9.4.3.2 
Severity ............................................................................................................61 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................61 
9.4.3.4 
Treatment Given for Adverse Event ................................................................61 
9.4.3.5 
Outcome of the Adverse Event ........................................................................61 
9.4.4 
Adjudication Committees .......................................................................................62 
9.5 
Procedures for Handling Special Situations ..................................................................62 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................62 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............63 
9.5.3 
Dosing Errors .........................................................................................................63 
9.5.4 
Contraception and Pregnancy .................................................................................63 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 64 
10.1 
Study Endpoints .............................................................................................................64 
10.1.1 
Efficacy Endpoints .................................................................................................64 
10.1.2 
Safety Endpoints .....................................................................................................64 
10.2 
Sample Size ....................................................................................................................65 
10.3 
Populations .....................................................................................................................65 
10.4 
Definition of Baseline ....................................................................................................65 
10.5 
Interim Analysis .............................................................................................................65 
10.6 
Planned Methods of Analysis ........................................................................................66 
10.6.1 
Demographic and Baseline Characteristics ............................................................66 
10.6.2 
Safety Analysis .......................................................................................................66 
10.6.3 
Efficacy Analysis ...................................................................................................67 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
8 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................67 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................67 
10.6.4.2 
Immunogenicity Analysis ................................................................................68 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 68 
11.1 
Informed Consent ..........................................................................................................68 
11.2 
Ethical Conduct of the Study .........................................................................................69 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................69 
11.4 
Patient Confidentiality ...................................................................................................69 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 70 
12.1 
Protocol Amendments ....................................................................................................70 
12.2 
Study Termination .........................................................................................................70 
12.3 
Study Documentation and Storage ................................................................................70 
12.4 
Study Monitoring ...........................................................................................................71 
12.5 
Language ........................................................................................................................71 
12.6 
Compensation for Injury ................................................................................................71 
13. 
REFERENCES ................................................................................................................ 72 
14. 
APPENDICES ................................................................................................................. 74 
Appendix A 
Schedule of Procedures ....................................................................................75 
Appendix B 
List of Laboratory Analytes .............................................................................81 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................83 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......85 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics .........................................................45 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the 
Lower Limit of Normal (x2) or < 100,000/mm3 (x1)* ..........................................48 
Table 3 
Actions in Patients with Low Platelet Count .........................................................54 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence ...................................................................................58 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms ...............29 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ....................................31 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen ...............33 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
 
10 April 2017 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
8 - France 
Amendment Date: 
10 April 2017 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 7 dated 3 February 2017:  
1. To update the platelet safety monitoring rules shown in Table 3. 
2. To assess acute pancreatitis in medical history in Group 2 patients. 
3. Added archive blood sample for potential gene sequencing related to 
hypertriglyceridemia (Group 2 if not available from index study). 
4  Added Troponin I and platelet bound autoantibody testing at baseline (may be done) to 
provide added patient safety; blood viscosity (may be done) to assess potential benefit of 
ISIS 304801 administration; and platelet aggregation (may be done) to assess platelet 
function. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol, additions are 
indicated as underline and deletions are indicated as strikethrough: 
Protocol 
Section 
Description of Change 
Rationale 
Section 3.4.3 
Post-
Treatment 
The post-treatment evaluation period is at least 26 weeks and consists of at 
least 69 Study Center visits on Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 
(Weeks 53, 54, 55, 56, 57, 58, and 71 may be conducted by a home healthcare 
nurse). 
 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
10 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Section 5.1 
Inclusion 
Criteria 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the 
following criteria in order to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement ≥ 
880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of the 
following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-causing 
genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical history. 
Note: testing of LPL activity should not be performed to confirm 
eligibility for the study 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-
CS16 index study  
4. 
Able and willing to participate in a 78-week study 
To clarify that 
either genetics or 
LPL activity can 
be used as an 
inclusion criteria 
and that LPL 
activity should not 
be performed 
unless already in 
medical history 
6.1.2 
Treatment 
Period 
During the treatment period, patients will report to the study center for clinic 
visits a minimum of 5 times during Weeks 1-52 (see Schedule of Procedures in 
Appendix A).  Study Drug will be administered once weekly unless the patient is 
on a biweekly dosing schedule for safety reasons (Section 8.1).  Collection and 
measurement of vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, blood viscosity, volanesorsen 
plasma concentrations, immunogenicity (IM) testing, platelet aggregation, 
liver/spleen MRI, ECGs, echocardiograms and quality of life assessments will 
be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary 
counseling will be reinforced at intervals throughout the treatment and follow-up 
period and all patients will complete a daily food diary for one week prior to their 
quarterly visit.  All blood and urine samples should be collected prior to 
volanesorsen administration.  Blood sampling at Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 
11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 
34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51 may be 
conducted by a home healthcare nurse.  Approval for study procedures to be 
conducted by a home healthcare nurse on other outpatient visit days will 
require prior approval by the Sponsor.  Patients must be fasted prior to drawing 
all blood samples and samples drawn locally should also be sent to the central 
laboratory for analysis whenever possible.  Every effort should be made to 
ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  
Dosing instructions and training will be provided to the patient where applicable. 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure  
6.1.4 Post-
Treatment 
Period 
After completion of the Week 52 visit assessments, patients will enter the at 
least 26-week post-treatment evaluation period or will participate in an 
expanded access program pending approval by the IRBs/IEC, and the 
appropriate regulatory authorities.  The 26-week period consists of at least 69 
Study Center visits on Weeks 53, 54,55, 56, 57, 58, 65, 71, and 78 (Weeks 53, 
54, 55, 56, 57, 58, and 71 may be conducted by a home healthcare nurse), as 
outlined in the Schedule of Procedures in Appendix A. 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
 
10 April 2017 
 
11 
Protocol 
Section 
Description of Change 
Rationale 
6.2.1 
Laboratory 
Assessments 
Each time a hematology lab is drawn and sent to the central laboratory for 
analysis an additional sample should be collected in parallel and analyzed 
locally.  In the event that both the central and local sample are unreportable 
(e.g., due to hemolyzed or clumped blood samples) another sample must be 
repeated within 1-week and the result must be reviewed by the Investigator and 
confirmed to be acceptable before dosing can continue.  All platelet count 
results will be promptly reviewed by the Investigator to determine if the count 
has met a stopping rule, or the dose reduction rule of 100,000/mm3, and 
determined not to have met a stopping rule before dosing can continue or the 
dose pause rule of 75,000/mm3. 
If there is no reportable platelet count within 14 days of the last platelet count, 
the Investigator will contact the patient to hold dosing until a new platelet count 
is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to ensure 
that the count has not met the stopping rule and to determine whether the rate 
of decline is suggestive that the patient could be approaching the dose pause 
rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited 
fashion to the Sponsor. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 
dose exposure, 
and treatment 
recommendations 
6.2.10 Chart 
Review for 
Incidents of 
Acute 
Pancreatitis in 
Medical 
History 
(Group 2) 
Added 
6.2.10 Chart Review for Incidents of Acute Pancreatitis in Medical History 
(Group 2) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up 
to 5 years prior to screening and information relating to these events will be 
collected for independent adjudication. 
To assess acute 
pancreatitis in 
medical history in 
Group 2 patients 
8.1 
Volanesorsen 
Administration 
Removed 
Every effort should be made to ensure the previous week’s dose is given 7 
days prior to a scheduled clinic visit. 
Dosing 
recommendations 
provided in 
updated 
monitoring and 
drug 
administration 
updates 
8.5.2 Safety 
Monitoring for 
Platelet Count 
Results 
Actions to be taken in the event of reduced platelet count are shown in Table 23 
in Section 8.6.3.  
Monitor every 1 week unless otherwise specified. 
Study Drug administration is contingent on the availability of the immediately 
preceding test result.  An interpretable platelet value must be available within 7 
days prior to dosing.  Only the study doctor or qualified designee can authorize 
continued Study Drug administration based on an acceptable platelet value.  
Patients should not administer a dose until they have been contacted by their 
study doctor or designee and told that it is acceptable to dose.  Authorization to 
dose must be documented in the patient’s medical records. 
Due to the 1 to 2-year study duration it is anticipated that patients may 
undertake travel including vacations, which may impede weekly platelet 
monitoring.  In some situations, it may be possible to arrange for local 
laboratory testing or use of the home healthcare service at their temporary 
location.  The intent is to maintain weekly platelet monitoring and dosing where 
possible, as well as Investigator site contact with the study patients.  However, 
if the above options are not possible, a temporary interruption of study 
treatment will be planned with a prompt blood draw upon the patient’s return 
which must be reported and reviewed by the Investigator prior to the patient 
resuming dosing. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 
dose exposure, 
and treatment 
recommendations 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
12 
Protocol 
Section 
Description of Change 
Rationale 
8.5.2 Safety 
Monitoring for 
Platelet Count 
Results 
Continued 
The tests outlined in Table 2 should also be performed as soon as possible.  
Additional lab tests will be determined by the Sponsor Medical Monitor or 
designee in consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited 
fashion to the Sponsor (See also Stopping Rules Section 8.6.3). 
Table 2 Labs to Be Performed in the Event of a Platelet Count Less than the 
Lower Limit of Normal (x2) or < 100,000/mm3 (x1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) of 
platelet count less than the lower limit of normal or who have any 1 occurrence 
of platelets < 100,000/mm3.  Labs only need to be performed once.  Labs may 
be collected over multiple visits, if blood requirements are a concern, as per 
Investigator discretion. 
Note: 
The following labs may change as additional data is assessed, and 
sites will be updated regarding any changes. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 
dose exposure, 
and treatment 
recommendation
s 
 
Added Table 2: 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central 
lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
13 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet Count 
Results 
Actions to be taken in the event of a low platelet count are summarized in 
Table 23 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with 
major bleeding or clinically-relevant non-major bleeding (defined below; 
Schulman et al. 2005), dosing of a patient with volanesorsen will be stopped 
permanently.  The follow-up schedule for any events meeting this stopping 
criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a rate of decline 
≥ 50% between two consecutive assessments, irrespective of the platelet level, 
or a platelet count less than 75,000/mm3 that occurs while the patient is on 
dosing at 300 mg every 2 weeks or 150 mg every week then dosing of a patient 
with volanesorsen will be stopped permanently.  Platelet count will be monitored 
as outlined in Table 3. daily until 2 successive values show improvement then 
monitored every 2-3 days until platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count is 
less than 2550,000/mm3.  Recovery in platelet count may be accelerated by 
administration of high dose steroids.  Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg 
daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d 
for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note:  may require continuation with oral steroids after methylprednisolone).  In 
order to reduce the unlikely but potential increased risk of pancreatitis during 
the period of corticosteroid therapy, triglyceride levels will be monitored weekly, 
and AE monitoring will continue, during corticosteroid treatment and the 
laboratory alert will be changed from an increase of 2,000 to 500 mg/dL during 
that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of 
major bleeding or clinically-relevant non-major bleeding (defined below; 
Schulman et al. 2005), dosing of a patient with volanesorsen should be 
suspended temporarily until the platelet count has recovered to > 100,000/mm3.  
If dosing is continued it should be at a reduced dose frequency of 300 mg every 
2 weeks or a reduced dose of 150 mg per week (refer to Section 8.7).  The 
suitability of the patient for continued dosing will be determined by the 
Investigator in consultation with the Study Medical Monitor and will be based on 
factors such as the original rate of decline in the patient’s platelet count, 
whether any bleeding events were experienced by the patient, and the speed of 
recovery of platelet count upon holding of dosing. 
If after the first dosing rechallenge the platelet count again falls below 
75,000/mm3, then dosing of the patient with Study Drug will be stopped 
permanently. 
Following a rechallenge platelet count should be tested every week until count 
is stable. 
Any unreportable platelet count result must be rechecked and determined not to 
have met a stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, 
the Investigator will contact the patient to hold dosing until a new platelet count 
is obtained and reviewed. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
14 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet Count 
Results 
Continued 
Table 23 
Actions in Patients with Low Platelet Count 
Platelet Count 
on Rx 
Drug Dose 
Monitoring 
Normal range, 
> 140K/mm3 
Study Drug administration is 
contingent on the availability 
of the immediately preceding 
test result.  An interpretable 
platelet value must be 
available within 7 days prior 
to dosing.  Only the study 
doctor or qualified designee 
can authorize continued 
Study Drug administration 
based on an acceptable 
platelet value.  Patients 
should not administer a dose 
until they have been 
contacted by their study 
doctor or designee and told 
that it is acceptable to dose.  
Authorization to dose must 
be documented in the 
patient’s medical records. 
No action 
Monitor every 1 week 
unless otherwise 
specified 
Obtain additional lab 
tests (Table 2) if 
2 occurrences 
consecutive or non-
consecutive) of 
platelet count 140K - 
> 100K/mm3 or 
1 occurrence of 
platelet count 
≤100K/mm3.  Labs 
only need to be 
performed once.  Labs 
may be collected over 
multiple visits, if blood 
requirements are a 
concern, as per 
Investigator discretion 
Monitor every 2 weeks 
> 100K/mm3-
140K/mm3 
Weekly 300 mg Study Drug 
administration No action 
Closer observation 
Monitor every 1 week 
until stable* 
75K-100K/mm3 - 
75K/mm3 
Permanently reduce dose 
frequency to 300 mg every 
2 weeks or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 1 week 
50K-75K/mm3 - 
50K/mm3 
If occurs while on dose of 
300 mg every 2 weeks or 
150 mg every week then 
permanently discontinue 
Study Drug, otherwise dose 
pause. 
When platelet count returns 
to > 100K/mm3 restart 
dosing at dose frequency of 
300 mg every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor 
Closer observation 
Monitor every 
2-3 days until 
2 successive values 
are > 75K/mm3 then 
monitor every 
1 weekshow 
improvement 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/ 
anticoagulant 
medication 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
 
 


ISIS 304801-CS7 
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15 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet Count 
Results 
Continued 
Table 23 
Actions in Patients with Low Platelet Count Continued 
Platelet Count 
on Rx 
Drug Dose 
Monitoring 
25K-< 50K/mm3 
or a rate of 
decline ≥ 50% 
between 
two consecutive 
assessments, 
irrespective of 
the platelet level 
Permanently discontinue 
Study Drug 
Closer observation 
• Monitor daily until 
2 successive values 
show improvement 
then monitor every 
2-3 days until 
2 successive values 
are > 75K/mm3 then 
monitor every 1 week 
platelet count stable 
• Patient should be 
evaluated by a 
hematologist to 
provide diagnostic 
and therapeutic 
management 
• Steroids 
recommended if 
platelet count is 
< 50K/mm3*.  It is 
strongly 
recommended that, 
unless the patient has 
a medical 
contraindication to 
receiving 
glucocorticoids, the 
patient receives 
glucocorticoid therapy 
to reverse the platelet 
decline.   
• Monitor triglyceride 
levels weekly and 
continue AE 
monitoring during 
steroid therapy 
• Discontinue 
antiplatelet 
agents/NSAIDS/antico
agulant medication 
while platelet count 
< 50K/mm3 if possible 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
 
 


ISIS 304801-CS7 
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Amendment 8 
Protocol - France 
10 April 2017 
 
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Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping Rules 
for Platelet 
Count Results 
Continued 
Table 23 
Actions in Patients with Low Platelet Count Continued 
Platelet Count 
on Rx 
Drug Dose 
Monitoring 
< 25K/mm3 
Permanently discontinue 
Study Drug 
Closer observation: 
Monitor daily until 
2 successive values 
show improvement then 
monitor every 2-3 days 
until platelet count 
stable 
Steroids 
recommended** 
Consider need for 
hospitalization and 
referral to hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoa
gulant medication while 
platelet count 
< 50K/mm3 if possible 
* At least 3 consecutive values measured weekly that are stable as 
determined by the Sponsor Medical Monitor and > 100,000/mm3 
**Recovery in platelet count may be accelerated by administration of high 
dose steroids.  Treatment guidelines for immune thrombocytopenia 
(Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days 
every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 
weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days 
(note:  may require continuation with oral steroids after methyl 
prednisolone).  In order to reduce the unlikely but potential increased risk 
of pancreatitis during the period of corticosteroid therapy, triglyceride 
levels will be monitored weekly, and AE monitoring will continue, during 
corticosteroid treatment and the laboratory alert will be changed from an 
increase of 2,000 to 500 mg/dL during that period. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
Synopsis 
10.1.1 Efficacy 
Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the 
treatment period 
• Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-HDL-C, apoB, HDL-C, 
apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Change in blood viscosity (may be evaluated) 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
To assess 
potential benefit of 
ISIS 304801 
administration 
 
 


ISIS 304801-CS7 
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Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
10.1.2 Safety 
Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
• Platelet aggregation (may be evaluated) 
To assess platelet 
function following 
ISIS 304801 
administration 
Appendix A 
Removed Week 2.5 
 
CBC with Differential 
c 
Each time a hematology lab is drawn and sent to the central laboratory 
for analysis an additional sample should be collected in parallel and 
analyzed locally. In the event that both the central and local sample are 
unreportable (e.g., due to hemolyzed or clumped blood samples) 
another sample must be repeated within 1 week and the result must be 
reviewed by the Investigator and confirmed to be acceptable before 
dosing can continue.  All platelet count results will be promptly reviewed 
by the Investigator to determine if the count has met a stopping rule, or 
the dose reduction rule of 100,000/mm3, or the and determined not to 
have met a stopping rule before dosing can continue.  If there is no 
reportable platelet count within 14 days of the last platelet count, the 
Investigator will contact the patient to hold dosing until a new platelet 
count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that the count has not 
met the stopping rule and to determine whether the rate of decline is 
suggestive that the patient could be approaching the dose pause rule of 
75,000/mm3.  In the event of any platelet count less than 50,000/mm3 or 
a rate of decline ≥ 50% between two consecutive assessments, 
irrespective of the platelet level, then dosing of a patient with Study Drug 
(ISIS 304801 or placebo) will be stopped permanently.  Any case of a 
platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 
 
Added:  
Medical Historyq 
Blood Viscosityr 
Platelet Aggregationr 
Platelet Bound Autoantibodiesr 
Archive blood sample for potential gene sequencing related to 
hypertriglyceridemia (Group 2 if not available from index study) g 
Xs 
q 
Patient charts will be reviewed in order to collect data for events of 
acute pancreatitis or suspected pancreatitis in the patient’s medical 
history.  Chart review may be conducted at any time during the study.  
These events will be adjudicated in the same manner as for events of 
pancreatitis during the study 
r 
May be done.  Blood viscosity and platelet aggregation in 
volanesorsen-treatment naïve patients only 
s 
Platelets are assessed each calendar week, visits do not have 
specified windows to allow flexibility of scheduling 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
Medical history, 
blood viscosity and 
potential gene 
sequencing to 
assess potential 
benefit of 
ISIS 304801 
administration 
Platelet 
aggregation to 
assess platelet 
function following 
ISIS 304801 
administration 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
 
10 April 2017 
 
18 
Protocol 
Section 
Description of Change 
Rationale 
Appendix B 
Added: 
Troponin I2 
CK-MB2 
Platelet Bound Autoantibodies3 
Blood Viscosity3 
Platelet Aggregation3 
 
2 
All abnormal troponin samples will be rerun at the central laboratory and 
also analyzed for CK-MB 
3 
May be done 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
Blood viscosity to 
assess potential 
benefit of 
ISIS 304801 
administration 
Platelet 
aggregation to 
assess platelet 
function following 
ISIS 304801 
administration 
 
 


ISIS 304801-CS7 
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Amendment 8 
Protocol - France 
10 April 2017 
 
19 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will enter an at least 
26-week post-treatment evaluation period or will participate in an expanded 
access program pending approval by the IRBs/IEC, and the appropriate 
regulatory authorities. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet 
the following criteria in order to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of 
the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical 
history.  Note:  testing of LPL activity should not be performed 
to confirm eligibility for the study 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 index study  
4. 
Able and willing to participate in a 78-week study 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and FSH levels in the 
postmenopausal range for the laboratory involved), abstinent*, or if 
engaged in sexual relations of child-bearing potential, patient is 
using an acceptable contraceptive method (refer to Section 6.3.1) 
from time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria: 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of Qualification 
b. HbA1c ≥ 9.0% at Qualification 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage 
or addition of new medication within 12 weeks of Qualification [with 
the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to Qualification 
4. History within 6 months of Qualification of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of Qualification 
 
 


ISIS 304801-CS7 
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Protocol - France 
10 April 2017 
 
21 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
5. Any of the following laboratory values at Qualification 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Qualification 
d. 
LDL-C > 130 mg/dL at Qualification 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding 
diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Qualification 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully 
treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1 month of Qualification, or 5 half-lives of investigational agent, 
whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
22 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to Qualification and dose 
and regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
Qualification 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
Qualification unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to Qualification and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to Qualification and dose and regimen expected to 
remain constant during the treatment period 
f. Glybera gene therapy within 2 years prior to Qualification 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
Qualification and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to Qualification and dose and regimen expected 
to remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to Qualification or planned 
during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to 
Qualification (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of 
> 499 mL within 60 days of Qualification 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, including new or worsening of existing 
condition, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the 
patient participating in or completing the study 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
23 
PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A 
• 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
• 
An at least 26-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, blood 
viscosity, volanesorsen plasma concentrations, immunogenicity (IM) testing, 
platelet aggregation, liver/spleen magnetic resonance imaging (MRI), ECGs, 
echocardiograms and quality of life assessments will be performed according 
to the schedule of procedures in Appendix A.  Dietary counseling will be 
repeated at intervals throughout the treatment and follow-up period and a 
daily food/drink diary will be completed for the week prior to each quarterly 
visit by each patient.  Following the Week 52 visit, patients will enter an at 
least 26-week post-treatment evaluation period or will participate in an 
expanded access program pending approval by the IRBs/IEC, and the 
appropriate regulatory authorities. 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
24 
PROTOCOL SYNOPSIS Continued 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


ISIS 304801-CS7 
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Protocol - France 
10 April 2017 
 
25 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 78* 
Safety, efficacy, PK and PD assessments 
* If needed, the post-treatment follow-up 
period will be extended (with patients 
monitored every 6 weeks) until apoC-III 
levels return to baseline values 


ISIS 304801-CS7 
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Amendment 8 
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10 April 2017 
 
26 
STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
27 
STUDY GLOSSARY Continued 
Abbreviation/Acronym 
Definition 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


ISIS 304801-CS7 
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10 April 2017 
 
28 
1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the 
RNase H1-mediated degradation of the apoC-III mRNA, thus preventing production of the 
apoC-III protein.  Maximal antisense-mediated reduction of target mRNA levels is typically 
greater than 90% of control levels in sensitive tissues (Crooke and Bennett 1996;  
Zhang et al. 2010).  Furthermore, reduction in target mRNA levels using this approach correlates 
directly with a subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive) 
A  G  C T T
C  T T G T C C A G C 
T T T A T 
Phosphorothioate 
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter an at least 26-week post-treatment evaluation period 
or will participate in an expanded access program pending approval by the IRBs/IEC, and the 
appropriate regulatory authorities. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Qualification 
A qualification period of up to 2 weeks (unless approved by the Sponsor) is given to complete 
qualification assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and 
Appendix A. 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is at least 26 weeks and consists of at least 9 Study Center 
visits on Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 (Weeks 53, 54, 55, 56, 57, 58, and 71 may 
be conducted by a home healthcare nurse). 
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 


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recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any 
study-specific procedures or evaluations related to this open-label study are performed.   
During the qualification period, the eligibility of the patient to enroll in the open-label study will 
be determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may 
be used for qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient 
identification number will be used to identify the patient throughout the extension trial and must 
be used on all study documentation related to that patient.  The patient identification number 
must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all qualification assessments 
have been completed and after the Investigator has verified that they are eligible per criteria in 
Sections 5.1 and 5.2.  No patient may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the following 
criteria in order to enter into the open-label Study: 


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a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
supported by documentation of at least 1 of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤ 20% of normal in medical history.  Note: 
testing of LPL activity should not be performed to confirm eligibility for the 
study. 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 index 
study 
4. Able and willing to participate in a 78-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of Qualification 
b. HbA1c ≥ 9.0% at Qualification 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of Qualification [with the exception of ± 10 units of 
insulin]) 


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d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to Qualification 
4. History within 6 months of Qualification of acute or unstable cardiac ischemia 
(myocardial infarction, acute coronary syndrome, new onset angina), stroke, transient 
ischemic attack or unstable congestive cardiac failure requiring a change in medication or 
major surgery within 3 months of Qualification 
5. Any of the following laboratory values at Qualification 
a. Hepatic: 
• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• ALT > 2.0 x ULN 
• AST > 2.0 x ULN 
b. Renal: 
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick.  In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs 
• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick.  In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field 
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Qualification 
d. LDL-C > 130 mg/dL at Qualification 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding diathesis or 
coagulopathy or clinically-significant abnormality in coagulation parameters at 
Qualification 
8. History of heart failure with NYHA greater than Class II 


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9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1 month 
of Qualification, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable 
dose for at least 3 months prior to Qualification and dose and regimen expected to 
remain constant during the treatment period.  Patients taking OTC omega-3 fatty 
acids should make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to Qualification 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Qualification 
unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to Qualification and dose and regimen expected to 
remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
Qualification and dose and regimen expected to remain constant during the treatment 
period 
f. Glybera gene therapy within 2 years prior to Qualification 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to Qualification and regular clinical monitoring 
is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to Qualification and dose and regimen expected to remain constant during the 
treatment period 
i. Plasma apheresis within 4 weeks prior to Qualification or planned during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to Qualification (Occasional 
or intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of > 499 mL within 
60 days of Qualification 


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16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or 
placebo) 
17. Have any other conditions, including new or worsening of existing condition, which, in 
the opinion of the Investigator or the Sponsor would make the patient unsuitable for 
inclusion, or could interfere with the patient participating in or completing the study 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification  
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, blood viscosity, volanesorsen 
plasma concentrations, immunogenicity (IM) testing, platelet aggregation, liver/spleen MRI, 
ECGs, echocardiograms and quality of life assessments will be performed according to the 
schedule of procedures in Appendix A.  Adverse events at the injection site should be collected 
as adverse events.  Dietary counseling will be reinforced at intervals throughout the treatment 
and follow-up period and all patients will complete a daily food diary for one week prior to their 
quarterly visit.  All blood and urine samples should be collected prior to volanesorsen 
administration.  Blood sampling at Weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 
21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 
49, 50, and 51 may be conducted by a home healthcare nurse.  Approval for study procedures to 
be conducted by a home healthcare nurse on other outpatient visit days will require prior 
approval by the Sponsor.  Patients must be fasted prior to drawing all blood samples and samples 
drawn locally should also be sent to the central laboratory for analysis whenever possible.  
Dosing instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 


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6.1.3 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.4 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the at least 26-week 
post-treatment evaluation period or will participate in an expanded access program pending 
approval by the IRBs/IEC, and the appropriate regulatory authorities.  The 26-week period 
consists of at least 9 Study Center visits on Weeks 53, 54, 55, 56, 57, 58, 65, 71, and 78 
(Weeks 53, 54, 55, 56, 57, 58, and 71 may be conducted by a home healthcare nurse), as outlined 
in the Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1 week and the result must be reviewed by the Investigator and 
confirmed to be acceptable before dosing can continue.  All platelet count results will be 
promptly reviewed by the Investigator to determine if the count has met a stopping rule, or the 
dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 


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6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 roll over patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, 
Week 65, and Week 78. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, Week 65, and Week 78. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, Week 65, and Week 78. 


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2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior 
to screening and information relating to these events will be collected for independent 
adjudication.  
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent† or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 


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includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
* Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are 
not acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2 °C to 8 °C and be protected from light. 
 


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Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL 
Volume/Formulation 
1.5 mL solution per PFS 
Dose 
300 mg once weekly 
Route of Administration 
SC 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8.
TREATMENT OF PATIENTS
8.1 
Volanesorsen Administration
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 


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8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  


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Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3. 
Monitor every 1 week unless otherwise specified. 
Study Drug administration is contingent on the availability of the immediately preceding test 
result.  An interpretable platelet value must be available within 7 days prior to dosing.  Only the 
study doctor or qualified designee can authorize continued Study Drug administration based on 
an acceptable platelet value.  Patients should not administer a dose until they have been 
contacted by their study doctor or designee and told that it is acceptable to dose.  Authorization 
to dose must be documented in the patient’s medical records. 
Due to the 1 to 2-year study duration it is anticipated that patients may undertake travel including 
vacations, which may impede weekly platelet monitoring.  In some situations, it may be possible 
to arrange for local laboratory testing or use of the home healthcare service at their temporary 
location.  The intent is to maintain weekly platelet monitoring and dosing where possible, as well 
as Investigator site contact with the study patients.  However, if the above options are not 
possible, a temporary interruption of study treatment will be planned with a prompt blood draw 


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upon the patient’s return which must be reported and reviewed by the Investigator prior to the 
patient resuming dosing. 
The tests outlined in Table 2 should also be performed as soon as possible.  Additional lab tests 
will be determined by the Sponsor Medical Monitor or designee in consultation with the 
Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower 
Limit of Normal (x2) or < 100,000/mm3 (x1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) of platelet count less 
than the lower limit of normal or who have any 1 occurrence of platelets < 100,000/mm3.  Labs 
only need to be performed once.  Labs may be collected over multiple visits, if blood 
requirements are a concern, as per investigator discretion. 
Note: The following labs may change as additional data is assessed, and sites will be updated 
regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 


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8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or 
clinically-relevant, non-major bleeding events (which are defined in Section 8.6.3), for example 
excess bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event 
occurs, the Investigator must notify the Sponsor Medical Monitor and additional testing of 
coagulation parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), 
INR and platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 


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o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as one in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1 week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 


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The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 


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8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a rate of decline ≥ 50% between two 
consecutive assessments, irrespective of the platelet level, or a platelet count less than 
75,000/mm3 that occurs while the patient is on dosing at 300 mg every 2 weeks, then dosing of a 
patient with volanesorsen will be stopped permanently.  Platelet count will be monitored as 
outlined in Table 3. 


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Administration of steroids is recommended for patients whose platelet count is less than 
50,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note:  may require continuation with oral steroids after methylprednisolone).  In order to reduce 
the unlikely but potential increased risk of pancreatitis during the period of corticosteroid 
therapy, triglyceride levels will be monitored weekly, and AE monitoring will continue, during 
corticosteroid treatment and the laboratory alert will be changed from an increase of 2,000 to 
500 mg/dL during that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks (refer to Section 8.7).  The suitability of the patient for continued dosing will be 
determined by the Investigator in consultation with the Study Medical Monitor and will be based 
on factors such as the original rate of decline in the patient’s platelet count, whether any bleeding 
events were experienced by the patient, and the speed of recovery of platelet count upon holding 
of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
 


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Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
 
Study Drug administration is contingent on 
the availability of the immediately 
preceding test result.  An interpretable 
platelet value must be available within 
7 days prior to dosing.  Only the study 
doctor or qualified designee can authorize 
continued Study Drug administration 
based on an acceptable platelet value.  
Patients should not administer a dose until 
they have been contacted by their study 
doctor or designee and told that it is 
acceptable to dose.  Authorization to dose 
must be documented in the patient’s 
medical records. 
Monitor every 1 week unless 
otherwise specified 
Obtain additional lab tests  
(Table 2) if 2 occurrences 
consecutive or non-consecutive of 
platelet count 140K - > 100K/mm3 
or 1 occurrence of platelet count 
≤ 100K/mm3.  Labs only need to 
be performed once.  Labs may be 
collected over multiple visits, if 
blood requirements are a concern, 
as per Investigator discretion. 
> 100K/mm3 
Weekly 300 mg Study Drug administration 
 
100K/mm3 - >75K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks  
 
75K/mm3 - >50K/mm3 
• 
If occurs while on dose of 300 mg 
every 2 weeks then permanently 
discontinue Study Drug, otherwise 
dose pause. 
• 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks 
only if approved by Sponsor 
Medical Monitor 
• 
Monitor every 2-3 days until 
2 successive values are 
> 75K/mm3 then monitor every 
1 week 
• 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
< 50K/mm3 or a rate of 
decline ≥ 50% between 
two consecutive 
assessments, irrespective of 
the platelet level 
Permanently discontinue Study Drug   
• Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
2 successive values are 
> 75K/mm3 then monitor every 
1 week 
• Patient should be evaluated by a 
hematologist to provide 
diagnostic and therapeutic 
management 
• Steroids recommended if platelet 
count is < 50K/mm3*.  It is 
strongly recommended that, 
unless the patient has a medical 
contraindication to receiving 
glucocorticoids, the patient 
receives glucocorticoid therapy 
to reverse the platelet decline.   
• Monitor triglyceride levels weekly 
and continue AE monitoring 
during steroid therapy  
• Discontinue antiplatelet agents/ 
NSAIDS/ anticoagulant 
medication while platelet count 
is< 50K/mm3 if possible 
 


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Table 3 
Actions in Patients with Low Platelet Count Continued 
Legend: 
* 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methyl prednisolone).  In order 
to reduce the unlikely but potential increased risk of pancreatitis during the period of corticosteroid therapy, 
triglyceride levels will be monitored weekly, and AE monitoring will continue, during corticosteroid treatment and 
the laboratory alert will be changed from an increase of 2,000 to 500 mg/dL during that period. 
 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 3 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 
schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in Table 3 in Section 8.6.3 for the first 6 weeks after 
discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3), the next platelet count should be taken within at least 6 weeks so that patients 
are monitored for at least 12 weeks after discontinuing Study Drug.  Patients should also be 
strongly encouraged to attend applicable landmark visits at Weeks 12, 13, 25, 26, and 50, 52 
(calculated based on the time elapsed since Day 1) to collect fasting lipid panels and conduct 
safety assessments in accordance with the Schedule of Procedures in Appendix A.  Any patient 


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who discontinues treatment after Week 44 should also be strongly encouraged to attend a final 
follow-up visit (Week 78 visit assessments) approximately 26 weeks after their last dose of 
Study Drug, in addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 3 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 
6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  
Patients should also be encouraged to undergo a final follow-up visit (Week 78, see Appendix A) 
prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 


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8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline Qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 78 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 


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9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 


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9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 


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9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 78 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 78 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
 
 


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• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 


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• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 


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9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 


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physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Change in blood viscosity (may be evaluated) 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 


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• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
• Platelet aggregation (may be evaluated) 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active 
Study Drug and have a baseline TG assessment.  The FAS represents the practically-feasible 
intent-to-treat (ITT) population as delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline will be the last non-missing assessment prior to the first dose of Study Drug.  Details 
will be provided in the SAP. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 


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10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group of the index studies for 
patients on active Study Drug in the ISIS 304801-CS6 or ISIS 304801-CS16 index studies, and 
pooled treatment naïve group which includes patients on placebo in index studies.  Where 
appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided tests 
with 5% Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will 
be assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK 
endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group and overall.  The patient disposition will be summarized by treatment group and 
overall.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
and overall. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term 
and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 


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10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group.  Response rate of patients with fasting plasma TG 
< 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and 
Month 12 will be summarized.  Response analysis will also be conducted using a range of fasting 
plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group for other fasting lipid measures including non-HDL-C, apoB, 
HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 
2 patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the 
index study will receive the first treatment of volanesorsen (single-dose PK), while patients who 
received volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these 
patients reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time 
taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under 
the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration 
(CL0-24h /F) will be calculated from CL0-24h /F = Actual Dose/AUC0-24h.  Mean residence time 
(MRT) from time zero to 24 hours after the SC administration will be calculated from the 
equation, MRT0-24h = AUMC0-24h /AUC0-24h, where AUMC0-24h is the area under the moment 
plasma concentration-time curve from time zero to 24 hours after the SC administration.  Other 
PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 


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Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the last ADA sample 
collection day, and subject - peak titer if applicable, will be listed by their prior treatment in 
Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by treatment group.  Furthermore, onset and titer of the ADA 
response, if applicable, will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., %change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 


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informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 


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No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 


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13. 
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Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
74 
 
 
 
 
 
 
 
14. 
APPENDICES 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
75 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
Qualification through Treatment Period 
Post-Treatment Follow-up 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
 
10 April 2017 
 
76 
Appendix A Schedule of Procedures – Qualification through Treatment Period 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to -
7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight (+ height on Day 1 only) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
Xk 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
CBC with Differentialb 
X 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
Serum Lipid Panel 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Blood viscosityr 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Platelet aggregationr 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Coagulation (aPTT, PT, INR) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
hsCRP, HbA1c, FPG, and de-lipidated free glycerol 
Xn 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Plasma PK - Volanesorsen 
 
Xl 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
FSH (women only, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Archived Serum & Plasma Samplese 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Troponin Io 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Bound Autoantibodiesr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archive blood sample for potential gene sequencing 
related to hypertriglyceridemia (Group 2 if not 
available from index study)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
77 
Appendix A Schedule of Procedures - Qualification through Treatment Period Continued 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to -1 
Wk 
1 
W
k 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to 
 -7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Urinalysisc 
X 
Xm 
 
X 
 
X 
 
 
Xm 
 
Xm 
 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Genetic testing for FCS diagnosis (if not 
available in medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Food/Drink Diary (quarterly)h 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Diet/Alcohol Counselingi 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
78 
Appendix A Schedule of Procedures – Post-Treatment Follow-up  
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Informed Consent 
 
 
 
 
 
Outpatient Visit 
Xj 
Xj 
X 
Xj 
X 
Inclusion/Exclusion Criteria 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
Echocardiography 
 
 
 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialb 
Xs 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
Serum Pregnancy Testd 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplese 
 
 
X 
 
X 
Troponin Io 
 
 
 
 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
79 
Appendix A Schedule of Procedures – Post-Treatment Follow-up Continued 
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 
540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Urinalysisc 
 
Xm 
Xm 
Xm 
Xm 
Fundus Photographyf 
 
 
 
 
 
Genetic testing for FCS diagnosis 
(if not available in medical 
history)g 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
80 
Appendix A Schedule of Procedures Continued 
a 
Qualification procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should 
be collected in parallel and analyzed locally.  In the event that both the central and local sample are unreportable 
(e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 1 week and the 
result must be reviewed by the Investigator and confirmed to be acceptable before dosing can continue.  All 
platelet count results will be promptly reviewed by the Investigator to determine if the count has met a stopping 
rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3.  Any case of a platelet 
count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  
During treatment period urine and blood samples will be collected prior to Study Drug administration.  Does not 
apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or 
adverse events (e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of 
kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug 
(Group 2 ISIS 304801-CS16 roll over patients) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
g 
Genetic testing can be conducted for study Qualification (Group 2 ISIS 304801-CS16 roll over patients); genetic 
testing will only be conducted if allowed in the geographic region and only after the patient has given specific 
written informed consent for genetic testing 
h 
In addition to diary, patients will be contacted at random times during the study to review their current eating and 
drinking habits 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will 
also be performed by dietician or study personnel 
j 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as 
arranged by the Study Center personnel 
k 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
l 
Full or abbreviated PK profile (see Appendix C) 
m 
Expanded urinalysis (see Appendix B) 
n 
HbA1c only 
o 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
p 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until 
apoC-III levels return to baseline values 
q 
Patient charts will be reviewed in order to collect data for events of acute pancreatitis or suspected pancreatitis in 
the patient’s medical history.  Chart review may be conducted at any time during the study.  These events will be 
adjudicated in the same manner as for events of pancreatitis during the study 
r 
May be done.  Blood viscosity and platelet aggregation in volanesorsen-treatment naïve patients only 
s 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
81 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
82 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
Troponin I2 
• 
CK-MB2 
• 
Platelet Bound 
Autoantibodies3 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
• 
Blood viscosity3 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination4 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
Platelet Function 
• 
Platelet aggregation3 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
3 
May be done 
4 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
83 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
84 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose Pre-dose Pre-dose Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
Post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
85 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
86 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
87 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 8 
Protocol - France 
10 April 2017 
 
88 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 7 – 7 April 2017 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 30480 l-CS7 
Protocol 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 7 
7 April 2017 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 7 - 7 April 2017 
Protocol History: 
Original Protocol: 
Protocol Amendment 1 : 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Protocol Amendment 5: 
Protocol Amendment 6: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010
MD, MBA 
28 August 2015 
2 February 2016 
22 April 2016 
9 May 2016 
6 June 2016 
6 July 2016 
18 November 2016 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 7 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
7 April 2017 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 7 
Date: 
7 April 2017 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 7 April 2017, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.....................................................................................................10 
PROTOCOL SYNOPSIS ............................................................................................................22 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................28 
STUDY GLOSSARY ...................................................................................................................29 
1. 
OBJECTIVES ..................................................................................................................31 
2. 
BACKGROUND AND RATIONALE ...........................................................................31 
2.1 
Overview of Disease ......................................................................................................31 
2.2 
Therapeutic Rationale ....................................................................................................32 
2.3 
Volanesorsen ..................................................................................................................33 
2.3.1 
Mechanism of Action .............................................................................................33 
2.3.2 
Chemistry ...............................................................................................................34 
2.3.3 
Preclinical Experience ............................................................................................35 
2.3.4 
Clinical Experience ................................................................................................36 
2.4 
Rationale for Dose and Schedule of Administration .....................................................37 
3. 
EXPERIMENTAL PLAN ...............................................................................................38 
3.1 
Study Design ..................................................................................................................38 
3.2 
Number of Study Centers ..............................................................................................38 
3.3 
Number of Patients ........................................................................................................38 
3.4 
Overall Study Duration and Follow-up .........................................................................38 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification ....................................................................................38 
3.4.2 
Group 3 Patients (did not participate in an index study):   
Screening/Qualification ..........................................................................................38 
3.4.3 
Treatment ................................................................................................................38 
3.4.4 
Post-Treatment .......................................................................................................39 
3.5 
End-of-Study ..................................................................................................................39 
3.6 
Data and Safety Monitoring Board ................................................................................39 
4. 
PATIENT ENROLLMENT ............................................................................................39 
4.1 
Screening/Qualification .................................................................................................39 
4.2 
Enrollment .....................................................................................................................40 
5. 
PATIENT ELIGIBILITY ...............................................................................................40 
5.1 
Inclusion Criteria ...........................................................................................................40 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-CS16) 
Index Study Roll-over Patients ......................................................................................41 
6. 
STUDY PROCEDURES .................................................................................................44 
6.1 
Study Schedule ..............................................................................................................44 
6.1.1 
Qualification (Groups 1 and 2) ...............................................................................44 


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6.1.2 
Screening and Qualification (Group 3) ..................................................................44 
6.1.3 
Treatment Period ....................................................................................................44 
6.1.4 
Extended Treatment Period ....................................................................................45 
6.1.5 
Pharmacokinetic (PK) Subgroup ............................................................................45 
6.1.6 
Post-Treatment Period ............................................................................................46 
6.2 
Additional Study Assessments .......................................................................................46 
6.2.1 
Laboratory Assessments .........................................................................................46 
6.2.2 
Physical Exams and Vital Signs .............................................................................46 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................46 
6.2.2.2 
Lipemia Retinalis .............................................................................................47 
6.2.3 
Echocardiography ...................................................................................................47 
6.2.4 
ECG ........................................................................................................................47 
6.2.5 
MRI ........................................................................................................................47 
6.2.6 
Quality of Life Assessments ...................................................................................47 
6.2.7 
Disease Symptom Diary .........................................................................................47 
6.2.8 
Diet Monitoring ......................................................................................................47 
6.2.9 
Family History ........................................................................................................48 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History  
(Group 2 and 3) ......................................................................................................48 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................48 
6.3.1 
Contraception Requirements ..................................................................................48 
6.3.2 
Other Requirements ................................................................................................49 
7. 
STUDY DRUG .................................................................................................................49 
7.1 
Volanesorsen Description ..............................................................................................49 
7.2 
Packaging and Labeling .................................................................................................50 
7.3 
Study Drug Accountability ............................................................................................50 
8. 
TREATMENT OF PATIENTS ......................................................................................50 
8.1 
Volanesorsen Administration ........................................................................................50 
8.2 
Other Protocol-Required Drugs .....................................................................................50 
8.3 
Other Protocol-Required Treatment Procedures ............................................................50 
8.4 
Treatment Precautions ...................................................................................................50 
8.5 
Safety Monitoring Rules ................................................................................................50 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................51 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................52 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................54 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................54 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................54 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........54 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................55 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................55 


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8.5.9 
Acute Pancreatitis ...................................................................................................56 
8.6 
Stopping Rules ...............................................................................................................56 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................57 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................57 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................57 
8.7 
Adjustment of Dose Frequency .....................................................................................60 
8.8 
Discontinuation of Study Treatment ..............................................................................60 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................60 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .60 
8.9 
Withdrawal of Patients from the Study ..........................................................................61 
8.10 
Concomitant Therapy and Procedures ...........................................................................61 
8.10.1 
Concomitant Therapy .............................................................................................61 
8.10.2 
Concomitant Procedures .........................................................................................62 
8.11 
Treatment Compliance ...................................................................................................62 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .......................62 
9.1 
Sponsor Review of Safety Information .........................................................................62 
9.2 
Regulatory Requirements ..............................................................................................62 
9.3 
Definitions .....................................................................................................................63 
9.3.1 
Adverse Event ........................................................................................................63 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................64 
9.3.3 
Serious Adverse Event (SAE) ................................................................................64 
9.4 
Monitoring and Recording Adverse Events ...................................................................64 
9.4.1 
Serious Adverse Events ..........................................................................................64 
9.4.2 
Non-Serious Adverse Events ..................................................................................65 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................65 
9.4.3.1 
Relationship to the Study Drug ........................................................................65 
9.4.3.2 
Severity ............................................................................................................65 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................66 
9.4.3.4 
Treatment Given for Adverse Event ................................................................66 
9.4.3.5 
Outcome of the Adverse Event ........................................................................66 
9.4.4 
Adjudication Committees .......................................................................................67 
9.5 
Procedures for Handling Special Situations ..................................................................67 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................67 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............67 
9.5.3 
Dosing Errors .........................................................................................................68 
9.5.4 
Contraception and Pregnancy .................................................................................68 
10. 
STATISTICAL CONSIDERATIONS ...........................................................................69 
10.1 
Study Endpoints .............................................................................................................69 
10.1.1 
Efficacy Endpoints .................................................................................................69 
10.1.2 
Safety Endpoints .....................................................................................................69 


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10.2 
Sample Size ....................................................................................................................69 
10.3 
Populations .....................................................................................................................70 
10.4 
Definition of Baseline ....................................................................................................70 
10.5 
Interim Analysis .............................................................................................................70 
10.6 
Planned Methods of Analysis ........................................................................................70 
10.6.1 
Demographic and Baseline Characteristics ............................................................71 
10.6.2 
Safety Analysis .......................................................................................................71 
10.6.3 
Efficacy Analysis ...................................................................................................71 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................72 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................72 
10.6.4.2 
Immunogenicity Analysis ................................................................................72 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ..............................................73 
11.1 
Informed Consent ..........................................................................................................73 
11.2 
Ethical Conduct of the Study .........................................................................................73 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................74 
11.4 
Patient Confidentiality ...................................................................................................74 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................74 
12.1 
Protocol Amendments ....................................................................................................74 
12.2 
Study Termination .........................................................................................................75 
12.3 
Study Documentation and Storage ................................................................................75 
12.4 
Study Monitoring ...........................................................................................................75 
12.5 
Language ........................................................................................................................76 
12.6 
Compensation for Injury ................................................................................................76 
13. 
REFERENCES .................................................................................................................77 
14. 
APPENDICES ..................................................................................................................79 
Appendix A 
Schedule of Procedures ....................................................................................80 
Appendix B 
List of Laboratory Analytes .............................................................................86 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................88 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......90 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics .........................................................49 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the 
Lower Limit of Normal (x2) or < 100,000/mm3 (x1)* ..........................................53 
Table 3 
Actions in Patients with Low Platelet Count or Drop in Platelet Count ................59 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence ...................................................................................63 


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TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms ...............32 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides 
(MOE-Gapmer).  The sequence of volanesorsen is shown ....................................34 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen ...............36 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
10 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
7 
Amendment Date: 
7 April 2017 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 6 dated 18 November 2016: 
1. To update the platelet safety monitoring rules shown in Table 3. 
2. To add LPL activity of ≤ 20% of normal in medical history as an inclusion criteria for 
Group 2 and 3 patients as has been allowed for Group 1 patients. 
3. To add platelet count < lower limit of normal (LLN) for the central laboratory 
 (i.e., < 140,000/mm3) for Group 3 patients. 
4. To assess acute pancreatitis in medical history in Group 2 patients. 
5. Added archive blood sample for potential gene sequencing related to 
hypertriglyceridemia (Group 3; Group 2 if not available from index study) 
6. Added blood viscosity (may be done) to assess potential benefit of ISIS 304801 
administration and platelet aggregation (may be done) to assess platelet function. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol, additions are 
indicated as underline and deletions are indicated as strikethrough: 
Protocol 
Section 
Description of Change 
Rationale 
Section 3.4.4 
Post-
Treatment 
Was 
The post-treatment evaluation period is 13 weeks and consists of 4 Study 
Center visits on Weeks 54, 56, 58, and 65 (Weeks 54, 56, and 58 may be 
conducted by a home healthcare nurse). 
 
Is 
The post-treatment evaluation period is 13 weeks and consists of 7 Study 
Center visits on Weeks 53, 54, 55, 56, 57, 58, and 65 (Weeks 53, 54, 55, 
56, 57, and 58 may be conducted by a home healthcare nurse). 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure 


ISIS 304801-CS7 
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Amendment 7 
Protocol 
7 April 2017 
 
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Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Section 5.1 
Inclusion 
Criteria 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
Groups 2 and 3:  Patients must also meet the following criteria in order 
to enter into the open-label Study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG 
measurement ≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 
of the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in 
medical history.  Note: testing of LPL activity should not 
be performed to confirm eligibility for the study 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for 
the ISIS 304801-CS16 index study 
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label 
study 
To add LPL 
activity of ≤ 20% 
of normal in 
medical history 
as an inclusion 
criteria for 
Group 2 and 3 
patients as has 
been allowed for 
Group 1 patients 
Synopsis 
5.2 Exclusion 
Criteria for 
Group 3 
5. 
Any of the following laboratory values at Screening 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be  
≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or 
CKD-EPI formulas can be used instead of Cockcroft-Gault for 
estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Platelet count < lower limit of normal (LLN) for the central 
laboratory (i.e., < 140,000/mm3) 
dc. Cardiac Troponin I > ULN at Screening 
ed. LDL-C > 130 mg/dL at Screening 
fe. Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
To provide added 
patient safety 
regarding platelet 
count reductions, 
and ISIS 304801 
dose exposure  
 
 


ISIS 304801-CS7 
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Amendment 7 
Protocol 
7 April 2017 
 
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Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
6.1.3 
Treatment 
Period 
During the treatment period, patients will report to the study center for clinic 
visits a minimum of 5 times during Weeks 1-52 (see Schedule of 
Procedures in Appendix A).  Study Drug will be administered once weekly 
unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory 
parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, blood 
viscosity, volanesorsen plasma concentrations, immunogenicity (IM) 
testing, platelet aggregation, liver/spleen MRI, ECGs, echocardiograms 
and quality of life assessments will be performed according to the schedule 
of procedures in Appendix A.  Adverse events at the injection site should be 
collected as adverse events.  Dietary counseling will be reinforced at 
intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All 
blood and urine samples should be collected prior to volanesorsen 
administration.  Blood sampling at Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 
35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51 may be 
conducted by a home healthcare nurse.  Approval for study procedures to 
be conducted by a home healthcare nurse on other outpatient visit days will 
require prior approval by the Sponsor.  Patients must be fasted prior to 
drawing all blood samples and samples drawn locally should also be sent to 
the central laboratory for analysis whenever possible.  Every effort should 
be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit.  Dosing instructions and training will be provided to 
the patient where applicable. 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure  
6.14 Extended 
Treatment 
Period 
During the extended treatment period, patients will report to the study 
center for clinic visits during Weeks 54-104 (see Schedule of Procedures in 
Appendix A).  Study Drug will be administered once weekly unless the 
patient is on a biweekly dosing schedule for safety reasons (Section 8.1).  
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, volanesorsen plasma 
concentrations, IM testing, ECGs, and physical examinations will be 
performed according to the Schedule of Procedures in Appendix A.  
Adverse events at the injection site should be collected as adverse events.  
Dietary counseling will be reinforced at intervals throughout the extended 
treatment period.  All blood and urine samples should be collected prior to 
volanesorsen administration.  Blood sampling at Weeks 53, 54, 55, 56, 57, 
58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 79, 
80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 
100, 101, 102, and 103 may be conducted by a home healthcare nurse.  
Approval for study procedures to be conducted by a home healthcare nurse 
on other outpatient visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples and samples 
drawn locally should also be sent to the central laboratory for analysis 
whenever possible.  Every effort should be made to ensure the previous 
week’s dose is given 7 days prior to a scheduled clinic visit.  Dosing 
instructions and training will be provided to the patient where applicable. 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
13 
Protocol 
Section 
Description of Change 
Rationale 
6.1.6 
Post-Treatment 
Period 
After completion of the Week 52 visit assessments, patients will have the 
option of participating in an expanded access program or continuing dosing 
for up to an additional 52 weeks until an expanded access program is 
approved and available in their country as described in Section 6.1.4.  
Patients not participating in an expanded access program will enter the 
13-week post treatment evaluation period.  This 13-week post treatment 
evaluation period consists of 7 Study Center visits on Weeks 53, 54, 55, 
56, 57, and 58 (which may be conducted by a home healthcare nurse), and 
Week 65 as outlined in the Schedule of Procedures in Appendix A.  
Patients who complete, or terminate early from, the extended treatment 
period without subsequently participating in an expanded access program 
will enter a 13-week post treatment evaluation period consisting of 7 Study 
Center visits on Weeks 105, 106, 107, 108, 109, and 110 (which may be 
conducted by a home healthcare nurse), and Week 117 as outlined in the 
Schedule of Procedures in Appendix A. 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure 
6.2.1 
Laboratory 
Assessments 
Each time a hematology lab is drawn and sent to the central laboratory for 
analysis an additional sample should be collected in parallel and analyzed 
locally.  In the event that both the central and local sample are unreportable 
(e.g., due to hemolyzed or clumped blood samples) another sample must 
be repeated within 1-week and the result must be reviewed by the 
Investigator and confirmed to be acceptable before dosing can 
continue.  All platelet count results will be promptly reviewed by the 
Investigator to determine if the count has met a stopping rule, or the 
dose reduction rule of 100,000/mm3, and determined not to have met a 
stopping rule before dosing can continue or the dose pause rule of 
75,000/mm3. 
If there is no reportable platelet count within 14 days of the last platelet 
count, the Investigator will contact the patient to hold dosing until a new 
platelet count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to 
ensure that the count has not met the stopping rule and to determine 
whether the rate of decline is suggestive that the patient could be 
approaching the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an 
expedited fashion to the Sponsor. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
6.2.10 Chart 
Review for 
Incidents of 
Acute 
Pancreatitis in 
Medical History 
Added 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History 
(Group 2 and 3) 
To assess acute 
pancreatitis in 
medical history in 
Group 2 patients 
8.1 
Volanesorsen 
Administration 
Removed 
Every effort should be made to ensure the previous week’s dose is given 7 
days prior to a scheduled clinic visit. 
Dosing 
recommendations 
provided in 
updated 
monitoring and 
drug 
administration 
updates 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
14 
Protocol 
Section 
Description of Change 
Rationale 
8.5.2 Safety 
Monitoring for 
Platelet Count 
Results 
Actions to be taken in the event of reduced platelet count are shown in 
Table 3 in Section 8.6.3.  
Monitor every 1 week unless otherwise specified. 
Study Drug administration is contingent on the availability of the 
immediately preceding test result.  An interpretable platelet value 
must be available within 7 days prior to dosing.  Only the study doctor 
or qualified designee can authorize continued Study Drug 
administration based on an acceptable platelet value.  Patients should 
not administer a dose until they have been contacted by their study 
doctor or designee and told that it is acceptable to dose.  
Authorization to dose must be documented in the patient’s medical 
records. 
Due to the 1 to 2-year study duration it is anticipated that patients may 
undertake travel including vacations, which may impede weekly 
platelet monitoring.  In some situations, it may be possible to arrange 
for local laboratory testing or use of the home healthcare service at 
their temporary location.  The intent is to maintain weekly platelet 
monitoring and dosing where possible, as well as Investigator site 
contact with the study patients.  However, if the above options are not 
possible, a temporary interruption of study treatment will be planned 
with a prompt blood draw upon the patient’s return which must be 
reported and reviewed by the Investigator prior to the patient 
resuming dosing. 
The tests outlined in Table 2 should also be performed as soon as possible.  
Additional lab tests will be determined by the Sponsor Medical Monitor or 
designee in consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an 
expedited fashion to the Sponsor (See also Stopping Rules Section 8.6.3). 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
15 
Protocol 
Section 
Description of Change 
Rationale 
8.5.2 Safety 
Monitoring for 
Platelet Count 
Results 
Continued 
Table 2 Labs to Be Performed in the Event of a Platelet Count Less than 
the Lower Limit of Normal (x2) or < 100,000/mm3 (x1)*< 75,000/mm3 
*In patients who have any 2 occurrences (consecutive or non-
consecutive) of platelet count less than the lower limit of normal or 
who have any 1 occurrence of platelets < 100,000/mm3.  Labs only 
need to be performed once.  Labs may be collected over multiple 
visits, if blood requirements are a concern, as per Investigator 
discretion. 
Note: 
The following labs may change as additional data is assessed, 
and sites will be updated regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to 
central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
16 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Actions to be taken in the event of a low platelet count are summarized in 
Table 3 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with 
major bleeding or clinically-relevant non-major bleeding (defined below; 
Schulman et al. 2005), dosing of a patient with volanesorsen will be stopped 
permanently.  The follow-up schedule for any events meeting this stopping 
criterion will be determined by the Investigator in consultation with the 
Sponsor Medical Monitor.  
In the event of any platelet count less than 2550,000/mm3, or a platelet count 
less than 75,000/mm3 that occurs while the patient is on dosing at 300 mg 
every 2 weeks or 150 mg every week then dosing of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored 
as outlined in Table 3. daily until 2 successive values show improvement then 
monitored every 2-3 days until platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count 
is less than 2550,000/mm3.  Recovery in platelet count may be accelerated 
by administration of high dose steroids.  Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg 
daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5 2 mg/kg/d 
for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone).  
Triglyceride levels will be monitored weekly, and AE monitoring will continue, 
during cortiscosteroid treatment and the laboratory alert will be changed from 
an increase of 2,000 to 500 mg/dL during that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of 
major bleeding or clinically-relevant non-major bleeding (defined below; 
Schulman et al. 2005), dosing of a patient with volanesorsen should be 
suspended temporarily until the platelet count has recovered to 
> 100,000/mm3.  If dosing is continued it should be at a reduced dose 
frequency of 300 mg every 2 weeks or a reduced dose of 150 mg per week 
(refer to Section 8.7).  The suitability of the patient for continued dosing will 
be determined by the Investigator in consultation with the Study Medical 
Monitor and will be based on factors such as the original rate of decline in the 
patient’s platelet count, whether any bleeding events were experienced by 
the patient, and the speed of recovery of platelet count upon holding of 
dosing. 
If after the first dosing rechallenge the platelet count again falls below 
75,000/mm3, then dosing of the patient with Study Drug will be stopped 
permanently. 
Following a rechallenge platelet count should be tested every week until 
count is stable. 
Any unreportable platelet count result must be rechecked and determined not 
to have met a stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, 
the Investigator will contact the patient to hold dosing until a new platelet 
count is obtained and reviewed. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 
dose exposure, 
and treatment 
recommendations 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
17 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Was: 
Table 3 Actions in Patients with Low Platelet Count 
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
Normal range, 
> 140K/mm3 
No action 
Monitor every 2 weeks 
100K-
140K/mm3 
No action 
Closer observation 
Monitor every 1 week until 
stable* 
75K-
100K/mm3 
Permanently reduce 
dose frequency to 
300 mg every 2 weeks 
or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 1 week 
50K-75K/mm3 
If occurs while on dose 
of 300 mg every 
2 weeks or 150 mg 
every week then 
permanently 
discontinue Study Drug, 
otherwise dose pause. 
When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 
If occurs while on dose 
of 300 mg every 
2 weeks or 150 mg 
every week then 
permanently 
discontinue Study Drug, 
otherwise dose pause. 
When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor  
Closer observation 
Monitor daily until 
2 successive values show 
improvement then monitor 
every 2-3 days until platelet 
count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count < 50K/mm3 if possible 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 
dose exposure, 
and treatment 
recommendations 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
18 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Continued 
Was Continued 
 
Table 3 Actions in Patients with Low Platelet Count Continued 
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
< 25K/mm3 
Permanently 
discontinue 
Study Drug 
Closer observation: 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended** 
Consider need for 
hospitalization and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
At least 3 consecutive values measured weekly that are stable as 
determined by the Sponsor Medical Monitor and > 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration of high 
dose steroids.  Treatment guidelines for immune thrombocytopenia 
(Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days 
every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 
weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days (note:  
may require continuation with oral steroids after methyl prednisolone) 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
19 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet Count 
Results 
Continued 
Is 
 
Table 3 Actions in Patients with Low Platelet Count or Drop in Platelet 
Count 
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
 
Study Drug administration 
is contingent on the 
availability of the 
immediately preceding 
test result.  An 
interpretable platelet 
value must be available 
within 7 days prior to 
dosing.  Only the study 
doctor or qualified 
designee can authorize 
continued Study Drug 
administration based on 
an acceptable platelet 
value.  Patients should 
not administer a dose until 
they have been contacted 
by their study doctor or 
designee and told that it is 
acceptable to dose.  
Authorization to dose 
must be documented in 
the patient’s medical 
records. 
Monitor every 1 week 
unless otherwise 
specified 
Obtain additional lab tests 
(Table 2) if 2 occurrences 
consecutive or non-
consecutive) of platelet 
count 140K - > 100K/mm3 
or 1 occurrence of platelet 
count ≤ 100K/mm3.  Labs 
only need to be performed 
once.  Labs may be 
collected over multiple 
visits, if blood requirements 
are a concern, as per 
Investigator discretion. 
> 100K/mm3 
Weekly 300 mg Study 
Drug administration 
100K/mm3 - 
> 75K/mm3 
Permanently reduce dose 
frequency to 300 mg 
every 2 weeks 
 
75K/mm3 - 
> 50K/mm3 
• If occurs while on dose 
of 300 mg every 
2 weeks then 
permanently 
discontinue Study Drug, 
otherwise dose pause 
• When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks only if 
approved by Sponsor 
Medical Monitor 
• 
Monitor every 2-3 days 
until 2 successive 
values are >75K/mm3 
then monitor every 
1 week 
• 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/ 
anticoagulant 
medication 
 
 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
20 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet Count 
Results 
Continued 
Table 3 Actions in Patients with Low Platelet Count or Drop in Platelet 
Count Continued 
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
≤ 50K/mm3 
Permanently discontinue 
Study Drug 
• Monitor daily until 
2 successive values show 
improvement then 
monitor every 2-3 days 
until 2 successive values 
are > 75K/mm3 then 
monitor every 1 week 
• Patient should be 
evaluated by a 
hematologist to provide 
diagnostic and 
therapeutic management 
• Steroids recommended*.  
It is strongly 
recommended that, 
unless the patient has a 
medical contraindication 
to receiving 
glucocorticoids, the 
patient receives 
glucocorticoid therapy to 
reverse the platelet 
decline.   
• Monitor triglyceride levels 
weekly and continue AE 
monitoring during steroid 
therapy 
• Discontinue antiplatelet 
agents/ NSAIDS/ 
anticoagulant medication 
while platelet count 
is< 50K/mm3 if possible 
* 
Recovery in platelet count may be accelerated by administration of high 
dose steroids.  Treatment guidelines for immune thrombocytopenia 
(Provan et al. 2010) recommend dexamethasone 40 mg daily for 4 days 
every 2-4 weeks for 1-4 cycles; prednis(ol)one 0.5-2 mg/kg/d for 2-
4 weeks then taper; or methylprednisolone 30 mg/kg/day for 7 days 
(note:  may require continuation with oral steroids after 
methylprednisolone) 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
9.4.1 Serious 
Adverse 
Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, 
all SAEs (regardless of their relationship to volanesorsen) should be 
reported to the Sponsor or designee within 24 hours of the Study Center’s 
first knowledge of the event.  The collection of SAEs will begin after the 
patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit (or Week 117 if 
patient enters the extended treatment period).  When the Investigator is 
reporting by telephone, it is important to speak to someone in person versus 
leaving a message.  An Initial Serious Adverse Event Form should be 
completed and a copy should be faxed to the Sponsor or designee. 
To provide 
consistent SAE 
reporting rules 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
21 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
10.1.1 
Efficacy 
Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the 
treatment period 
• Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-HDL-C, apoB, HDL-C, 
apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Change in blood viscosity (may be evaluated) 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
To assess 
potential benefit of 
ISIS 304801 
administration 
Synopsis 
10.1.2 Safety 
Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
• Platelet aggregation (may be evaluated) 
To assess platelet 
function following 
ISIS 304801 
administration 
Appendix A 
Removed Week 2.5 
CBC with Differential 
c 
Each time a hematology lab is drawn and sent to the central laboratory 
for analysis an additional sample should be collected in parallel and 
analyzed locally.  In the event that both the central and local sample are 
unreportable (e.g., due to hemolyzed or clumped blood samples) 
another sample must be repeated within 1 week and the result must be 
reviewed by the Investigator and confirmed to be acceptable and 
determined not to have met a stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet 
count, the Investigator will contact the patient to hold dosing until a new 
platelet count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that determine if the 
count has not met the a stopping rule, and to determine whether the 
rate of decline is suggestive that the patient could be approaching the 
or the dose reduction rule of 100,000/mm3, or the dose pause rule of 
75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be 
reported in an expedited fashion to the Sponsor 
Added:  Blood Viscosity and Platelet Aggregation 
e 
May be done.  Blood viscosity and platelet aggregation in 
volanesorsen-treatment naïve patients only 
Added:  Archive blood sample for potential gene sequencing related to 
hypertriglyceridemia (Group 3; Group 2 if not available from index study) 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
Blood viscosity 
and potential 
gene sequencing 
to assess 
potential benefit of 
ISIS 304801 
administration. 
Platelet 
aggregation to 
assess platelet 
function following 
ISIS 304801 
administration. 
Appendix B 
Added Blood Viscosity and Platelet Aggregation 
To assess 
potential benefit of 
ISIS 304801 
administration 
To assess platelet 
function following 
ISIS 304801 
administration 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
22 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will have the option of 
participating in an expanded access program or continuing dosing for up to 
an additional 52 weeks until an expanded access program is approved and 
available in their country.  Patients not participating in an expanded access 
program will enter a 13-week post-treatment evaluation period 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order 
to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of 
the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical 
history. Note: testing of LPL activity should not be performed to 
confirm eligibility for the study 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for 
the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label 
study  
4. 
Able and willing to participate in a 65-week study 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
23 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2  
(ISIS 304801-CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the 
opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage 
or addition of new medication within 12 weeks of screening [with the 
exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to screening 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
24 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) Continued 
4. History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of screening 
5. Any of the following laboratory values at Screening 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Platelet count < lower limit of normal (LLN) for the central 
laboratory (i.e., < 140,000/mm3) 
d. 
Cardiac Troponin I > ULN at Screening 
e. 
LDL-C > 130 mg/dL at Screening 
f. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully 
treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1 month of screening, or 5 half-lives of investigational agent, 
whichever is longer 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
25 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) Continued 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to screening and dose and 
regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
screening unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to screening and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to screening and dose and regimen expected to remain 
constant during the treatment period 
f. Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening and dose and regimen expected to 
remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to screening or planned during 
the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening 
(Occasional or intermittent use of over-the-counter medications will be 
allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of 
> 499 mL within 60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or the 
Sponsor would make the patient unsuitable for inclusion, or could 
interfere with the patient participating in or completing the study 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
26 
PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up to 
2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A 
• 
Group 3 patients (did not participate in an index study):  An up to 
8-week screening and qualification period, including a diet 
stabilization period of at least 6 weeks (screening and diet 
stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease 
management prior to screening).  Please refer to Section 6.1.2 and 
Appendix A 
• 
All patients: 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
Option to participate in an extended treatment period (up to an 
additional 52 weeks) 
o 
A 13-week post-treatment evaluation period or expanded 
access program 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, blood 
viscosity, volanesorsen plasma concentrations, immunogenicity (IM) testing, 
platelet aggregation, liver/spleen magnetic resonance imaging (MRI), ECGs, 
echocardiograms and quality of life assessments will be performed according 
to the schedule of procedures in Appendix A.  Dietary counseling will be 
repeated at intervals throughout the treatment and follow-up period and a 
daily food/drink diary will be completed for the week prior to each quarterly 
visit by each patient.  Following the Week 52 visit, patients will have the 
option of participating in an expanded access program or continuing dosing 
for up to an additional 52 weeks until an expanded access program is 
approved and available in their country.  Patients not participating in an 
expanded access program will enter the 13-week post-treatment evaluation 
period. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
27 
PROTOCOL SYNOPSIS Continued 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
28 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
SCREENING PERIOD 
Weeks -8 to -2 (Group 3 patients only) 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION (ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety 
assessments.  PK and PD/efficacy 
assessments at specified time points 
POST-TREATMENT 
EVALUATION PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD 
assessments 
Patients will have 
the option of 
participating in an 
expanded access 
program or 
continuing dosing 
for up to an 
additional 52 weeks 
until an expanded 
access program is 
approved and 
available in their 
country. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
29 
STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
glycosylphosphatidylinositol-anchored hdl-binding protein 1 
HAPI 
heritability and phenotype intervention 
HbA1c 
glycated hemoglobin 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein-cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein-cholesterol 
LMF1 
lipase maturation factor 1 
LPL 
lipoprotein lipase 
MACE 
major acute cardiovascular event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
no-observed-adverse-effect level 
non-HDL-C 
non-high-density lipoprotein-cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
triglyceride-rich lipoproteins 
ULN 
upper limit of normal 
VLDL 
very-low-density lipoprotein 
VLDL-C 
very-low-density lipoprotein-cholesterol 
VLDL-TG 
lipoprotein-triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive) 
A  G  C T T
C  T T G T C C A G C 
T T T A T 
Phosphorothioate 
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or  
ISIS 304801-CS16 index studies 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients will have the option of participating in an expanded access 
program or continuing dosing for up to an additional 52 weeks until an expanded access program 
is approved and available in their country.  Patients not participating in an expanded access 
program will enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification 
A period of up to 2 weeks (unless approved by the Sponsor) is given to complete qualification 
assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and Appendix A. 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification 
An up to 8-week screening and qualification period, including a diet stabilization period of at 
least 6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if 
the patient is following a diet for optimal control of TGs and disease management prior to 
screening.  Please refer to Section 6.1.2 and Appendix A. 
3.4.3 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 


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3.4.4 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 7 Study Center visits on 
Weeks 53, 54, 55, 56, 57, 58, and 65 (Weeks 53, 54, 55, 56, 57, and 58 may be conducted by a 
home healthcare nurse). 
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Screening/Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open-label study are performed.   
Groups 1 and 2 (Qualification):  During the qualification period, the eligibility of the patient to 
enroll in the open-label study will be determined.  Final assessments from the ISIS 304801-CS6 
or ISIS 304801-CS16 studies may be used for qualification.  A period of up to 2 weeks after 
completion of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the 
Sponsor) is given to complete qualification.  Qualified patients will retain the unique patient 
identification number that was assigned to them during the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies.  The patient identification number will be used to identify the 
patient throughout the extension trial and must be used on all study documentation related to that 
patient.  The patient identification number must remain constant throughout the extension trial. 
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered 
enrolled into the study and will be assigned a unique screening number before any study 
procedures, including screening procedures, are performed.  At the time of enrollment, patients 
will be assigned a unique patient identification number.  This number will be used to identify the 
patient throughout the trial and must be used on all study documentation related to that patient.  
The screening number and patient identification number must remain constant throughout the 
entire trial.  In the event the patient is re-consented and re-screened the patient must be given a 
new screening number.  Screening numbers and patient identification numbers, once assigned, 
will not be re-used. 


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4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all Screening (Group3) and 
qualification assessments have been completed and after the Investigator has verified that they 
are eligible per criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to 
enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
Groups 2 and 3:  Patients must also meet the following criteria in order to enter into the 
open-label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
supported by documentation of at least 1 of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤ 20% of normal in medical history.  Note: 
testing of LPL activity should not be performed to confirm eligibility for the study 
c. Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the  
 
ISIS 304801-CS16 index study 
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label study 
4. Able and willing to participate in a 65-week study 
 
 


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5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 
(ISIS 304801-CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 
Exclusion Criteria for Group 3 (patients who did not participate in an index study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of screening [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening 


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4. History within 6 months of screening of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack 
or unstable congestive cardiac failure requiring a change in medication or major surgery 
within 3 months of screening 
5. Any of the following laboratory values at Screening 
a. Hepatic: 
• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• ALT > 2.0 x ULN 
• AST > 2.0 x ULN 
b. Renal: 
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick.  In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs 
• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick.  In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field 
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. Platelet count < lower limit of normal (LLN) for the central laboratory (i.e., 
< 140,000/mm3) 
d. Cardiac Troponin I > ULN at Screening 
e. LDL-C > 130 mg/dL at Screening 
f. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 


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10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1-month 
of screening, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable 
dose for at least 3 months prior to screening and dose and regimen expected to remain 
constant during the treatment period.  Patients taking OTC omega-3 fatty acids should 
make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening unless 
approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to screening and dose and regimen expected to remain 
stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
screening and dose and regimen expected to remain constant during the treatment 
period 
f. Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to screening and regular clinical monitoring is 
performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to screening and dose and regimen expected to remain constant during the treatment 
period 
i. Plasma apheresis within 4 weeks prior to screening or planned during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 
60 days of screening 


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16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or 
placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the patient participating 
in or completing the study 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification (Groups 1 and 2) 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  An 8-week period, including a diet stabilization period of at least 
6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease management prior to screening) 
is given to perform the screening evaluations.  The qualification assessments will be performed 
at Week -2 to -1, ideally after patient eligibility has been determined, and on Study Day 1.  
Abnormal screening results may be retested for review by the Study Medical Monitor for 
eligibility purposes 
6.1.3 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, blood viscosity, volanesorsen plasma 
concentrations, immunogenicity (IM) testing, platelet aggregation, liver/spleen MRI, ECGs, 
echocardiograms and quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Adverse events at the injection site should be collected as adverse 
events.  Dietary counseling will be reinforced at intervals throughout the treatment and follow-up 
period and all patients will complete a daily food diary for one week prior to their quarterly visit.  
All blood and urine samples should be collected prior to volanesorsen administration.  Blood 
sampling at Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51 
may be conducted by a home healthcare nurse.  Approval for study procedures to be conducted 


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by a home healthcare nurse on other outpatient visit days will require prior approval by the 
Sponsor.  Patients must be fasted prior to drawing all blood samples and samples drawn locally 
should also be sent to the central laboratory for analysis whenever possible.  Dosing instructions 
and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.4 
Extended Treatment Period 
Patients will have the option of continuing dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country. 
During the extended treatment period, patients will report to the study center for clinic visits 
during Weeks 54-104 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, volanesorsen plasma concentrations, IM testing, 
ECGs, and physical examinations will be performed according to the Schedule of Procedures in 
Appendix A.  Adverse events at the injection site should be collected as adverse events.  Dietary 
counseling will be reinforced at intervals throughout the extended treatment period.  All blood 
and urine samples should be collected prior to volanesorsen administration.  Blood sampling at 
Weeks 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 
79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 
103 may be conducted by a home healthcare nurse.  Approval for study procedures to be 
conducted by a home healthcare nurse on other outpatient visit days will require prior approval 
by the Sponsor.  Patients must be fasted prior to drawing all blood samples and samples drawn 
locally should also be sent to the central laboratory for analysis whenever possible.  Dosing 
instructions and training will be provided to the patient where applicable. 
6.1.5 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 


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6.1.6 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of participating 
in an expanded access program or continuing dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country as described in 
Section 6.1.4.  Patients not participating in an expanded access program will enter the 13-week 
post-treatment evaluation period.  This 13-week post-treatment evaluation period consists of 
7 Study Center visits on Weeks 53, 54, 55, 56, 57, and 58 (which may be conducted by a home 
healthcare nurse), and Week 65 as outlined in the Schedule of Procedures in Appendix A.  
Patients who complete, or terminate early from, the extended treatment period without 
subsequently participating in an expanded access program will enter a 13-week post-treatment 
evaluation period consisting of 7 Study Center visits on Weeks 105, 106, 107, 108, 109, and 110 
(which may be conducted by a home healthcare nurse), and Week 117 as outlined in the 
Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and the result must be reviewed by the Investigator and 
confirmed to be acceptable before dosing can continue.  All platelet count results will be 
promptly reviewed by the Investigator to determine if the count has met a stopping rule, or the 
dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
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6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 roll-over patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65.  Patients in the Extended Treatment Period will have ECGs performed in triplicate at 
Week 76 and Week 104. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period (Week 65). 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service.  
Patients in the Extended Treatment Period will receive diet/alcohol counseling by 
qualified study personnel at clinic visits only. 


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3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet may be conducted randomly during the treatment and 
post treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.2.10 Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2 and 3) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior 
to screening and information relating to these events will be collected for independent 
adjudication. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent† or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 


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patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
* Note: A female condom and a male condom should not be used together as friction between 
the two can result in either product failing. 
† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2 to 8 °C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 


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7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8.
TREATMENT OF PATIENTS
8.1 
Volanesorsen Administration
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 


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assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 


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Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3.  
Monitor every 1 week unless otherwise specified. 
Study Drug administration is contingent on the availability of the immediately preceding test 
result.  An interpretable platelet value must be available within 7 days prior to dosing.  Only the 
study doctor or qualified designee can authorize continued Study Drug administration based on 
an acceptable platelet value.  Patients should not administer a dose until they have been 
contacted by their study doctor or designee and told that it is acceptable to dose.  Authorization 
to dose must be documented in the patient’s medical records. 
Due to the 1 to 2-year study duration it is anticipated that patients may undertake travel including 
vacations, which may impede weekly platelet monitoring.  In some situations, it may be possible 
to arrange for local laboratory testing or use of the home healthcare service at their temporary 
location.  The intent is to maintain weekly platelet monitoring and dosing where possible, as well 
as Investigator site contact with the study patients.  However, if the above options are not 
possible, a temporary interruption of study treatment will be planned with a prompt blood draw 
upon the patient’s return which must be reported and reviewed by the Investigator prior to the 
patient resuming dosing. 
The tests outlined in Table 2 should also be performed as soon as possible.  Additional lab tests 
will be determined by the Sponsor Medical Monitor or designee in consultation with the 
Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
 


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Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower 
Limit of Normal (x2) or < 100,000/mm3 (x1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) of platelet count less 
than the lower limit of normal or who have any 1 occurrence of platelets < 100,000/mm3.  Labs 
only need to be performed once.  Labs may be collected over multiple visits, if blood 
requirements are a concern, as per Investigator discretion. 
Note: The following labs may change as additional data is assessed, and sites will be updated 
regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 
 


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8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
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o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1-week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 


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The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event 
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 


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8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 
that occurs while the patient is on dosing at 300 mg every 2 weeks then dosing of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored as outlined in 
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Administration of steroids is recommended for patients whose platelet count is less than 
50,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone).  Triglyceride levels 
will be monitored weekly, and AE monitoring will continue, during cortiscosteroid treatment and 
the laboratory alert will be changed from an increase of 2,000 to 500 mg/dL during that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks (refer to Section 8.7).  The suitability of the patient for continued dosing will be 
determined by the Investigator in consultation with the Study Medical Monitor and will be based 
on factors such as the original rate of decline in the patient’s platelet count, whether any bleeding 
events were experienced by the patient, and the speed of recovery of platelet count upon holding 
of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
 


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Table 3 
Actions in Patients with Low Platelet Count or Drop in Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
 
Study Drug administration is 
contingent on the availability of the 
immediately preceding test result.  An 
interpretable platelet value must be 
available within 7 days prior to dosing.  
Only the study doctor or qualified 
designee can authorize continued 
Study Drug administration based on an 
acceptable platelet value.  Patients 
should not administer a dose until they 
have been contacted by their study 
doctor or designee and told that it is 
acceptable to dose.  Authorization to 
dose must be documented in the 
patient’s medical records. 
Monitor every 1 week unless otherwise 
specified 
 
Obtain additional lab tests (Table 2) if 
2 occurrences consecutive or non-
consecutive) of platelet count 140K - 
> 100K/mm3 or 1 occurrence of platelet 
count ≤ 100K/mm3.  Labs only need to be 
performed once.  Labs may be collected 
over multiple visits, if blood requirements 
are a concern, as per Investigator 
discretion. 
> 100K/mm3 
Weekly 300 mg Study Drug 
administration 
100K/mm3 - >75K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks 
 
75K/mm3 - >50K/mm3 
• If occurs while on dose of 300 mg 
every 2 weeks then permanently 
discontinue Study Drug, otherwise 
dose pause 
• When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks 
only if approved by Sponsor 
Medical Monitor 
• 
Monitor every 2-3 days until 
2 successive values are > 75K/mm3 
then monitor every 1 week 
• 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
≤ 50K/mm3 
Permanently discontinue Study Drug 
• Monitor daily until 2 successive values 
show improvement then monitor every 
2-3 days until 2 successive values are 
> 75K/mm3 then monitor every 1 week 
• Patient should be evaluated by a 
hematologist to provide diagnostic and 
therapeutic management 
• Steroids recommended*.  It is strongly 
recommended that, unless the patient 
has a medical contraindication to 
receiving glucocorticoids, the patient 
receives glucocorticoid therapy to 
reverse the platelet decline.   
• Monitor triglyceride levels weekly and 
continue AE monitoring during steroid 
therapy 
• Discontinue antiplatelet agents/ 
NSAIDS/ anticoagulant medication while 
platelet count is < 50K/mm3 if possible 
* 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or methylprednisolone 
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8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 3 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 
schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in in Section 8.6.3 for the first 6 weeks after discontinuing Study 
Drug.  Following this period, if the platelet count is stable (at least 3 consecutive values that are 
stable as determined by the Sponsor Medical Monitor and > 100,000/mm3), the next platelet 
count should be taken within at least 6 weeks so that patients are monitored for at least 12 weeks 
after discontinuing Study Drug.  Patients should also be strongly encouraged to attend applicable 
landmark visits at Weeks 12, 13, 25, 26, and 50, 52 (calculated based on the time elapsed since 
Day 1) to collect fasting lipid panels and conduct safety assessments in accordance with the 
Schedule of Procedures in Appendix A.  Any patient who discontinues treatment after Week 44 
should also be strongly encouraged to attend a final follow-up visit (Week 65 visit assessments) 
approximately 13 weeks after their last dose of Study Drug, in addition to the applicable 
landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 3 in 


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Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 
6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  
Patients should also be encouraged to undergo a final follow-up visit (Week 65 (or Week 117 if 
terminating from the Extended Treatment Follow-Up Period), see Appendix A) prior to leaving 
the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 


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recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 (or Week 117 if patient enters the extended treatment 
period) visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 


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E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 


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9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 


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begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit (or Week 117 if patient enters the 
extended treatment period).  When the Investigator is reporting by telephone, it is important to 
speak to someone in person versus leaving a message.  An Initial Serious Adverse Event Form 
should be completed and a copy should be faxed to the Sponsor or designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit 
(or Week 117 if patient enters the extended treatment period).  The Investigator will monitor 
each patient closely and record all observed or volunteered AEs on the Adverse Event Case 
Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 


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• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 


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• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
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9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Change in blood viscosity (may be evaluated) 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
• Platelet aggregation (may be evaluated) 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 


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10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active 
Study Drug and have a baseline TG assessment.  The FAS represents the practically-feasible 
intent-to-treat (ITT) population as delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification).  
For Group 3 patients, the baseline for fasting lipid measurements is defined as the average of 
Day 1 pre-dose assessment and the last measurement prior to Day 1 in this open-label study. 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study and 
Group 3 patients, baseline will be the last non-missing assessment prior to the first dose of 
Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group of the index studies for 
patients on active in the ISIS 304801-CS6 or ISIS 304801-CS16 index studies, and pooled 
treatment naive group which including patients on placebo in index studies and Group 3 patients.  


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Where appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided 
tests with 5% Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will 
be assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK 
endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group and overall.  The patient disposition will be summarized by treatment group and 
overall.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
and overall. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term 
and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group.  Response rate of patients with fasting plasma TG 
< 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and 
Month 12 will be summarized.  Response analysis will also be conducted using a range of fasting 
plasma TG thresholds for determination of responder status. 


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Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group for other fasting lipid measures including non-HDL-C, apoB, 
HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 2 
patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the index 
study (and all patients in Group 3) will receive the first treatment of volanesorsen (single-dose 
PK), while patients who received volanesorsen in the index studies had been on volanesorsen 
treatment for 12 months (ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data 
collected from these patients reflect steady-state PK.  The maximum observed drug 
concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  Area under the plasma concentration-time curve from time zero to 
24 hours (AUC0-24h) will be calculated using the linear trapezoidal rule.  Apparent systemic 
(plasma) clearance after SC administration (CL0-24h /F) will be calculated from  
CL0-24h/F = Actual Dose/AUC0-24h.  Mean residence time (MRT) from time zero to 24 hours after 
the SC administration will be calculated from the equation,  
MRT0-24h = AUMC0-24h/AUC0-24h, where AUMC0-24h is the area under the moment plasma 
concentration-time curve from time zero to 24 hours after the SC administration.  Other PK 
parameters, as appropriate, may be determined or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 


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treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the last ADA sample 
collection day, and subject - peak titer if applicable, will be listed by their prior treatment in 
Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by treatment group.  Furthermore, onset and titer of the ADA 
response, if applicable, will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 


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as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 


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the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 


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the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 


ISIS 304801-CS7 
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7 April 2017 
 
77 
13. 
REFERENCES 
Altmann KH, Fabbrot D, Dean NM, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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CONFIDENTIAL 
Amendment 7 
Protocol 
7 April 2017 
 
78 
Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


ISIS 304801-CS7 
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Protocol 
7 April 2017 
 
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14. 
APPENDICES 
 
 
 


ISIS 304801-CS7 
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7 April 2017 
 
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Appendix A 
Schedule of Procedures 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
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7 April 2017 
 
81 
Appendix A Schedule of Procedures 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-8 to 
 -2 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 44
9 
Visit Window+/- Days 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Physical Examination 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Blood Draw (Fasting)d 
Chemistry Panel 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC with Differentialc 
X 
X 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
X 
Serum Lipid Panel 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Blood viscositye 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Platelet aggregatione 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Coagulation (aPTT, PT, INR) 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
HbA1c 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Sedimentation Rate 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Troponin I 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Platelet Bound Autoantibodiese 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK - Volanesorsen 
 
 
Xn 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
FSH (women only, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testf 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
82 
Appendix A Schedule of Procedures Continued 
Study Period 
Screen/ 
Run Ina Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-8 to 
 -2 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
 
 
 
Wk 
25 
Wk 
26 
 
 
 
 
 
 
 
Wk 
50 
Wk 52 
or ET 
 
 
 
Study Day 
-56 to 
-15 
-14 to 
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Blood Draw 
(Fasting)d 
Archive blood sample for potential 
gene sequencing related to 
hypertriglyceridemia (Group 3; 
Group 2 if not available from index 
study)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Serum & Plasma 
Samplesg 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Urinalysisd 
X 
X 
Xo 
 
X 
 
X 
 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
Xo 
Fundus Photographyh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Genetic testing for FCS diagnosis (if 
not available in medical history)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Food/Drink Diary (quarterly)j 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Diet/Alcohol Counselingk 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Screening and Qualification (Group 3) procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Patient charts will be reviewed in order to collect data for events of acute pancreatitis or suspected pancreatitis in the patient’s medical history.  Chart review may be 
conducted at any time during the study.  These events will be adjudicated in the same manner as for events of pancreatitis during the study 
c 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally.  In the 
event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 1 week and 
the result must be reviewed by the Investigator and confirmed to be acceptable before dosing can continue.  All platelet count results will be promptly reviewed by the 
Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3.  Any case of a 
platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
 


ISIS 304801-CS7 
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Amendment 7 
Protocol 
 
7 April 2017 
 
83 
Appendix A Schedule of Procedures Continued 
Legend Text Continued 
d 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
e 
May be done.  Blood viscosity and platelet aggregation in volanesorsen-treatment naïve patients only 
f 
Females of childbearing potential only 
g 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of 
volanesorsen 
h 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 [ISIS 304801-CS16 roll-over patients] and 
Group 3) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
i 
Genetic testing can be conducted for study qualification (Group 2 [ISIS 304801-CS16 roll-over patients] and Group 3); genetic testing will only be conducted if 
allowed in the geographic region and only after the patient has given specific written informed consent for genetic testing 
j 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
k 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
l 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
m 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
n 
Full or abbreviated PK profile (see Appendix C) 
o 
Expanded urinalysis (see Appendix B) 
 
 


ISIS 304801-CS7 
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Amendment 7 
Protocol 
 
7 April 2017 
 
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Appendix A Schedule of Procedures – Extended Treatment Period 
Study Period 
Treatment Period 
Post-Treatment 
Follow-up 
Study Week 
Wk 54 
& 56 
Wk 
58 
Wk 60 
& 62 
Mo 15 
Wk 64 
Wk 66 
& 68 
Wk 
70 
Wk 72 
& 74 
Mo 18 
Wk 76 
Wk 78 
& 80 
Wk 
82 
Wk 84, 
86, & 88 
Mo 21 
Wk 90 
Wk 92 
& 94 
Wk 
96 
Wk 
98, 
100 & 
102 
Mo 24 
Wk 
104 
Wk 
106 
& 
108 
Wk 
110 
Mo 27 
Wk 
117 
Study Day 
372 & 
386 
400 414 & 
428  
442 
456 & 
470 
484 498 & 
512 
526 
540 & 
554 
56
8  
582, 596 
& 610 
624 
638 & 
652 
666 
680, 
694 & 
708 
722 
736  
& 
750 
764 
813 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Outpatient Visit 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
X 
Vital Signs (+ body weight) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis(including P/C ratio) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood Draw (Fasting)b 
Chemistry Panel 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CBC with Differentiala 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
X 
Serum Lipid Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Troponin I 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 304801c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-ISIS 304801 Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Serum Pregnancy Testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Weekly Study Drug: SC Injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diet/Alcohol Counselinge 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
85 
Appendix A Schedule of Procedures – Extended Treatment Period Continued 
Legend Text 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1 week and the result must be reviewed by the Investigator and confirmed to be acceptable before dosing can continue.  All platelet count results will be 
promptly reviewed by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 
75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration 
c 
Abbreviated PK collection (see Appendix C) 
d 
Females of childbearing potential only 
e 
To reinforce compliance to the diet and alcohol restrictions 
f 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
86 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
87 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Screening Tests (Group 3) 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (women only) 
• 
Serum βhCG (women 
only) 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
Troponin I2 
• 
CK-MB2 
• 
Platelet Bound 
Autoantibodies3 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
• 
Blood viscosity3 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination4 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
Platelet Function 
• 
Platelet aggregation3 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
3 
May be done 
4 
Will be performed on abnormal findings unless otherwise specified 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
88 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
89 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (Extended Treatment Period) 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Study Day 
D526 
D722 
D813 
Visit Window 
+/- Days 
2 
2 
7 
Time Point 
Pre-dose,  
Pre-dose 
Anytime 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
90 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
91 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
92 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol 
 
7 April 2017 
 
93 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 7 - France – 3 February 2017 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304801-CS7 
Protocol - France 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 7 
3 February 2017 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 7 - France - 3 February 2017 
Protocol History: 
Original Protocol: 
Protocol Amendment 1: 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Protocol Amendment 5: 
Protocol Amendment 6: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Co
Carlsbad, CA 9
MD, MBA 
28 August 2015 
2 February 2016 
22 April 2016 
9 May 2016 
6 June 2016 
19 August 2016 
16 September 2016 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 7 - France 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
, Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
3 February 2017 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 7 - France 
Date:  
 
3 February 2017 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 3 February 2017, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT...................................................................................................... 9 
PROTOCOL SYNOPSIS ........................................................................................................... 13 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 19 
STUDY GLOSSARY .................................................................................................................. 20 
1. 
OBJECTIVES ................................................................................................................. 22 
2. 
BACKGROUND AND RATIONALE .......................................................................... 22 
2.1 
Overview of Disease ......................................................................................................22 
2.2 
Therapeutic Rationale ....................................................................................................23 
2.3 
Volanesorsen ..................................................................................................................24 
2.3.1 
Mechanism of Action .............................................................................................24 
2.3.2 
Chemistry ...............................................................................................................25 
2.3.3 
Preclinical Experience ............................................................................................26 
2.3.4 
Clinical Experience ................................................................................................27 
2.4 
Rationale for Dose and Schedule of Administration .....................................................28 
3. 
EXPERIMENTAL PLAN .............................................................................................. 29 
3.1 
Study Design ..................................................................................................................29 
3.2 
Number of Study Centers ..............................................................................................29 
3.3 
Number of Patients ........................................................................................................29 
3.4 
Overall Study Duration and Follow-up .........................................................................29 
3.4.1 
Qualification ...........................................................................................................29 
3.4.2 
Treatment ................................................................................................................29 
3.4.3 
Post-Treatment .......................................................................................................29 
3.5 
End-of-Study ..................................................................................................................29 
3.6 
Data and Safety Monitoring Board ................................................................................29 
4. 
PATIENT ENROLLMENT ........................................................................................... 30 
4.1 
Qualification ..................................................................................................................30 
4.2 
Enrollment .....................................................................................................................30 
5. 
PATIENT ELIGIBILITY .............................................................................................. 30 
5.1 
Inclusion Criteria ...........................................................................................................30 
5.2 
Exclusion Criteria ..........................................................................................................31 
6. 
STUDY PROCEDURES ................................................................................................ 34 
6.1 
Study Schedule ..............................................................................................................34 
6.1.1 
Qualification ...........................................................................................................34 
6.1.2 
Treatment Period ....................................................................................................34 
6.1.3 
Pharmacokinetic (PK) Subgroup ............................................................................34 
6.1.4 
Post-Treatment Period ............................................................................................35 
6.2 
Additional Study Assessments .......................................................................................35 
6.2.1 
Laboratory Assessments .........................................................................................35 


ISIS 304801-CS7 
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Protocol - France 
3 February 2017 
 
6 
6.2.2 
Physical Exams and Vital Signs .............................................................................35 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................36 
6.2.2.2 
Lipemia Retinalis .............................................................................................36 
6.2.3 
Echocardiography ...................................................................................................36 
6.2.4 
ECG ........................................................................................................................36 
6.2.5 
MRI ........................................................................................................................36 
6.2.6 
Quality of Life Assessments ...................................................................................36 
6.2.7 
Disease Symptom Diary .........................................................................................36 
6.2.8 
Diet Monitoring ......................................................................................................36 
6.2.9 
Family History ........................................................................................................37 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................37 
6.3.1 
Contraception Requirements ..................................................................................37 
6.3.2 
Other Requirements ................................................................................................38 
7. 
STUDY DRUG ................................................................................................................ 38 
7.1 
Volanesorsen Description ..............................................................................................38 
7.2 
Packaging and Labeling .................................................................................................39 
7.3 
Study Drug Accountability ............................................................................................39 
8. 
TREATMENT OF PATIENTS ..................................................................................... 39 
8.1 
Volanesorsen Administration ........................................................................................39 
8.2 
Other Protocol-Required Drugs .....................................................................................39 
8.3 
Other Protocol-Required Treatment Procedures ............................................................39 
8.4 
Treatment Precautions ...................................................................................................39 
8.5 
Safety Monitoring Rules ................................................................................................39 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................40 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................41 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................41 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................41 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................42 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........42 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................42 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................43 
8.5.9 
Acute Pancreatitis ...................................................................................................44 
8.6 
Stopping Rules ...............................................................................................................44 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................44 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................45 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................45 
8.7 
Adjustment of Dose Frequency .....................................................................................47 
8.8 
Discontinuation of Study Treatment ..............................................................................48 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................48 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .48 


ISIS 304801-CS7 
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Amendment 7 
Protocol - France 
3 February 2017 
 
7 
8.9 
Withdrawal of Patients from the Study ..........................................................................49 
8.10 
Concomitant Therapy and Procedures ...........................................................................49 
8.10.1 
Concomitant Therapy .............................................................................................49 
8.10.2 
Concomitant Procedures .........................................................................................50 
8.11 
Treatment Compliance ...................................................................................................50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 50 
9.1 
Sponsor Review of Safety Information .........................................................................50 
9.2 
Regulatory Requirements ..............................................................................................50 
9.3 
Definitions .....................................................................................................................51 
9.3.1 
Adverse Event ........................................................................................................51 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................51 
9.3.3 
Serious Adverse Event (SAE) ................................................................................52 
9.4 
Monitoring and Recording Adverse Events ...................................................................52 
9.4.1 
Serious Adverse Events ..........................................................................................52 
9.4.2 
Non-Serious Adverse Events ..................................................................................53 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................53 
9.4.3.1 
Relationship to the Study Drug ........................................................................53 
9.4.3.2 
Severity ............................................................................................................53 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................54 
9.4.3.4 
Treatment Given for Adverse Event ................................................................54 
9.4.3.5 
Outcome of the Adverse Event ........................................................................54 
9.4.4 
Adjudication Committees .......................................................................................55 
9.5 
Procedures for Handling Special Situations ..................................................................55 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................55 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............55 
9.5.3 
Dosing Errors .........................................................................................................56 
9.5.4 
Contraception and Pregnancy .................................................................................56 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 57 
10.1 
Study Endpoints .............................................................................................................57 
10.1.1 
Efficacy Endpoints .................................................................................................57 
10.1.2 
Safety Endpoints .....................................................................................................57 
10.2 
Sample Size ....................................................................................................................57 
10.3 
Populations .....................................................................................................................57 
10.4 
Definition of Baseline ....................................................................................................58 
10.5 
Interim Analysis .............................................................................................................58 
10.6 
Planned Methods of Analysis ........................................................................................58 
10.6.1 
Demographic and Baseline Characteristics ............................................................59 
10.6.2 
Safety Analysis .......................................................................................................59 
10.6.3 
Efficacy Analysis ...................................................................................................59 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................60 


ISIS 304801-CS7 
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Protocol - France 
3 February 2017 
 
8 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................60 
10.6.4.2 
Immunogenicity Analysis ................................................................................60 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 61 
11.1 
Informed Consent ..........................................................................................................61 
11.2 
Ethical Conduct of the Study .........................................................................................61 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................61 
11.4 
Patient Confidentiality ...................................................................................................62 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 62 
12.1 
Protocol Amendments ....................................................................................................62 
12.2 
Study Termination .........................................................................................................62 
12.3 
Study Documentation and Storage ................................................................................63 
12.4 
Study Monitoring ...........................................................................................................63 
12.5 
Language ........................................................................................................................64 
12.6 
Compensation for Injury ................................................................................................64 
13. 
REFERENCES ................................................................................................................ 65 
14. 
APPENDICES ................................................................................................................. 67 
Appendix A 
Schedule of Procedures ....................................................................................68 
Appendix B 
List of Laboratory Analytes .............................................................................74 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................76 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......78 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics .........................................................38 
Table 2 
Actions in Patients with Low Platelet Count .........................................................47 
Table 3 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence ...................................................................................51 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms ...............23 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides   
(MOE-Gapmer).  The sequence of volanesorsen is shown ....................................25 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen ...............27 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 7
Protocol - France 
 
3 February 2017
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
7 - France 
Amendment Date: 
3 February 2017 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 6 dated 16 September 2016:  
1. To exclude enrollment of FCS patients in this open-label study who did not participate in 
the ISIS 304801-CS6 or ISIS 304801-CS16 index studies 
2. To add post heparin plasma LPL activity of ≤ 20% of normal in medical history as an 
inclusion criteria for ISIS 304801-CS16 (Group 2) patients as has been allowed for 
ISIS 304801–CS6 (Group 1) patients 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design.  
The following table provides a summary list of major changes to the protocol: 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis: 
Study Design 
3.1  Study Design 
Was 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS 
patients 
Group 3:  FCS patients who did not participate in the 
ISIS 304801-CS6 or ISIS 304801-CS16 index studies 
 
Is 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS 
patients 
To exclude 
enrollment of FCS 
patients who did 
not participate in 
an index study 
from this open 
label study 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 7
Protocol - France 
 
3 February 2017
 
10 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis: 
Study Population 
5.1  Inclusion Criteria 
Was 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 
or ISIS 304801-CS16 (index studies) with an acceptable 
safety profile, per Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria 
in order to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by 
documentation of lactescent serum (a creamy top layer 
after ultracentrifugation of a fasting blood sample) or 
documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome 
(Type 1 Hyperlipoproteinemia) by documentation of the 
following: 
• 
Confirmed homozygote, compound heterozygote or 
double heterozygote for known loss-of-function 
mutations in Type 1-causing genes (such as LPL, 
apoC-II, GPIHBP1, or LMF1) 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at 
Screening for the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this 
open-label study  
 
Is 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 
or ISIS 304801-CS16 (index studies) with an acceptable 
safety profile, per Sponsor and Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must 
also meet the following criteria in order to enter into the open-
label study: 
a. 
History of chylomicronemia as evidenced by 
documentation of lactescent serum (a creamy top layer 
after ultracentrifugation of a fasting blood sample) or 
documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome 
(Type 1 Hyperlipoproteinemia) by documentation of the 
following: 
• 
Confirmed homozygote, compound heterozygote or 
double heterozygote for known loss-of-function 
mutations in Type 1-causing genes (such as LPL, 
apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal 
in medical history 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for 
the ISIS 304801-CS16 index study  
To define the 
inclusion criteria 
for each group of 
patients. 
To add LPL activity 
of ≤ 20% of normal 
in medical history 
as an inclusion 
criteria for Group 2 
patients as has 
been allowed for 
Group 1 patients 
Protocol Synopsis:  
Study Population 
5.2  Exclusion Criteria 
Was (noted throughout Exclusion Criteria) 
Screening* 
*(Group 3) or Qualification (Groups 1 and 2) 
 
Is (noted throughout Exclusion Criteria) 
Qualification 
To distinguish that 
patients who are 
rolling over from an 
index study will 
have Qualification 
assessments  


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
11 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:  
Study Visit Schedule 
and Procedures 
3.4  Overall Study 
Duration and 
Follow-up 
Study Design and 
Treatment Schema 
Appendix A 
Was 
The study for an individual patient will generally consist of the 
following periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of 
up to 2 weeks (unless approved by the Sponsor).  Please 
refer to Section 4.1 and Appendix A. 
• 
Group 3 patients (did not participate in an index study):  An 
up to 8-week screening and qualification period, including a 
diet stabilization period of at least 6 weeks (screening and 
diet stabilization period may be reduced, per Sponsor 
approval, if the patient is following a diet for optimal control 
of TGs and disease management prior to screening).  
Please refer to Section 6.1.2 and Appendix A.  
• 
All patients:  
o 
A 52-week treatment period during which 
volanesorsen will be administered as a once weekly 
SC injection 
A 13-week post-treatment evaluation period 
 
Is 
The study for an individual patient will generally consist of the 
following periods: 
• 
A qualification period of up to 2 weeks (unless approved by 
the Sponsor).  Please refer to Section 4.1 and Appendix A.   
• 
A 52-week treatment period during which volanesorsen will 
be administered as a once weekly SC injection 
• 
A 13-week post-treatment evaluation period 
To remove FCS 
patients who did 
not participate in 
an index study 
from the study 
schedule 
4.1  
Screening/Qualification 
Was 
Groups 1 and 2 (Qualification):  During the qualification period, the 
eligibility of the patient to enroll in the open-label study will be 
determined.  Final assessments from the ISIS 304801-CS6 or 
ISIS 304801-CS16 studies may be used for qualification.  A period 
of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the 
Sponsor) is given to complete qualification.  Qualified patients will 
retain the unique patient identification number that was assigned 
to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index 
studies.  The patient identification number will be used to identify 
the patient throughout the extension trial and must be used on all 
study documentation related to that patient.  The patient 
identification number must remain constant throughout the 
extension trial. 
Group 3 (Screening and Qualification):  At the time of consent, the 
patient will be considered enrolled into the study and will be 
assigned a unique screening number before any study 
procedures, including screening procedures, are performed.  At 
the time of enrollment, patients will be assigned a unique patient 
identification number.  This number will be used to identify the 
patient throughout the trial and must be used on all study 
documentation related to that patient.  The screening number and 
patient identification number must remain constant throughout the 
entire trial.  In the event the patient is re-consented and re-
screened the patient must be given a new screening number.  
Screening numbers and patient identification numbers, once 
assigned, will not be re-used. 
To remove FCS 
patients who did 
not participate in 
an index study 
from Screening/ 
Qualification 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
12 
Protocol Section 
Description of Change 
Rationale 
4.1  
Screening/Qualification 
Continued 
Is 
During the qualification period, the eligibility of the patient to enroll 
in the open-label study will be determined.  Final assessments 
from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may be 
used for qualification.  A period of up to 2 weeks after completion 
of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies 
(unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient 
identification number that was assigned to them during the 
ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The 
patient identification number will be used to identify the patient 
throughout the extension trial and must be used on all study 
documentation related to that patient.  The patient identification 
number must remain constant throughout the extension trial. 
To remove FCS 
patients who did 
not participate in 
an index study 
from Screening/ 
Qualification 
6.1.1  Screening 
6.1.2  Screening and 
Qualification (Group 3) 
Was 
6.1.1 
Qualification (Groups 1 and 2) 
Please refer to Section 4.1 and Appendix A. 
 
6.1.2 
Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, 
patients must sign and date the informed consent form.  An 
8-week period, including a diet stabilization period of at least 
6 weeks (screening and diet stabilization period may be reduced, 
per Sponsor approval, if the patient is following a diet for optimal 
control of TGs and disease management prior to screening) is 
given to perform the screening evaluations.  The qualification 
assessments will be performed at Week -2 to -1, ideally after 
patient eligibility has been determined, and on Study Day 1.  
Abnormal screening results may be retested for review by the 
Study Medical Monitor for eligibility purposes 
 
Is 
6.1.1 
Qualification 
Please refer to Section 4.1 and Appendix A. 
To remove FCS 
patients who did 
not participate in 
an index study 
from Screening/ 
Qualification 
Section 10.3 
Populations 
Updated: 
Full Analysis Set (FAS):  All patients who are enrolled and 
received at least 1 dose of active Study Drug and have a baseline 
TG assessment.   
 
PK Population:  All patients who are enrolled, receive at least 
1 dose of volanesorsen, and have at least 1 post first dose PK 
sample collected, analyzed, and reported. 
Modified to 
include, in the 
FAS, only those 
patients that are 
randomized and 
dosed and have a 
baseline TG 
assessment and 
clarified the PK 
Population 
 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will enter an at least 
26-week post-treatment evaluation period or will participate in an expanded 
access program pending approval by the IRBs/IEC, and the appropriate 
regulatory authorities. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet 
the following criteria in order to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical 
history 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 index study  
4. 
Able and willing to participate in a 78-week study 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and FSH levels in the 
postmenopausal range for the laboratory involved), abstinent*, or if 
engaged in sexual relations of child-bearing potential, patient is 
using an acceptable contraceptive method (refer to Section 6.3.1) 
from time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria: 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of Qualification 
b. HbA1c ≥ 9.0% at Qualification 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage 
or addition of new medication within 12 weeks of Qualification [with 
the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to Qualification 
4. History within 6 months of Qualification of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of Qualification 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
5. Any of the following laboratory values at Qualification 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Qualification 
d. 
LDL-C > 130 mg/dL at Qualification 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding 
diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Qualification 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully 
treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1 month of Qualification, or 5 half-lives of investigational agent, 
whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria: Continued 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to Qualification and dose 
and regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
Qualification 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
Qualification unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to Qualification and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to Qualification and dose and regimen expected to 
remain constant during the treatment period 
f. Glybera gene therapy within 2 years prior to Qualification 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
Qualification and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to Qualification and dose and regimen expected 
to remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to Qualification or planned 
during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to 
Qualification (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of 
> 499 mL within 60 days of Qualification 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, including new or worsening of existing 
condition, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the 
patient participating in or completing the study 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
 
 


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PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A 
• 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
• 
An at least 26-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter an at least 26-week post-
treatment evaluation period or will participate in an expanded access program 
pending approval by the IRBs/IEC, and the appropriate regulatory authorities. 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
 
 
 


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PROTOCOL SYNOPSIS Continued 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 78* 
Safety, efficacy, PK and PD assessments 
* If needed, the post-treatment follow-up 
period will be extended (with patients 
monitored every 6 weeks) until apoC-III 
levels return to baseline values 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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STUDY GLOSSARY Continued 
Abbreviation/Acronym 
Definition 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the 
RNase H1-mediated degradation of the apoC-III mRNA, thus preventing production of the 
apoC-III protein.  Maximal antisense-mediated reduction of target mRNA levels is typically 
greater than 90% of control levels in sensitive tissues (Crooke and Bennett 1996;  
Zhang et al. 2010).  Furthermore, reduction in target mRNA levels using this approach correlates 
directly with a subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter an at least 26-week post-treatment evaluation period 
or will participate in an expanded access program pending approval by the IRBs/IEC, and the 
appropriate regulatory authorities. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Qualification 
A qualification period of up to 2 weeks (unless approved by the Sponsor) is given to complete 
qualification assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and 
Appendix A. 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is at least 26 weeks and consists of at least 6 Study Center 
visits on Weeks 54, 56, 58, 65, 71, and 78 (Weeks 54, 56, 58, and 71 may be conducted by a 
home healthcare nurse). 
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 


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recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any 
study-specific procedures or evaluations related to this open-label study are performed.   
During the qualification period, the eligibility of the patient to enroll in the open-label study will 
be determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may 
be used for qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient 
identification number will be used to identify the patient throughout the extension trial and must 
be used on all study documentation related to that patient.  The patient identification number 
must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all qualification assessments 
have been completed and after the Investigator has verified that they are eligible per criteria in 
Sections 5.1 and 5.2.  No patient may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the following 
criteria in order to enter into the open-label Study: 


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a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤ 20% of normal in medical history 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 index 
study 
4. Able and willing to participate in a 78-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of Qualification 
b. HbA1c ≥ 9.0% at Qualification 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of Qualification [with the exception of ± 10 units of 
insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units of insulin) 


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e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to Qualification 
4. History within 6 months of Qualification of acute or unstable cardiac ischemia 
(myocardial infarction, acute coronary syndrome, new onset angina), stroke, transient 
ischemic attack or unstable congestive cardiac failure requiring a change in medication or 
major surgery within 3 months of Qualification 
5. Any of the following laboratory values at Qualification 
a. Hepatic: 
• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• ALT > 2.0 x ULN 
• AST > 2.0 x ULN 
b. Renal: 
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick.  In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs 
• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick.  In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field 
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Qualification 
d. LDL-C > 130 mg/dL at Qualification 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding diathesis or 
coagulopathy or clinically-significant abnormality in coagulation parameters at 
Qualification 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 


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10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1 month 
of Qualification, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable 
dose for at least 3 months prior to Qualification and dose and regimen expected to 
remain constant during the treatment period.  Patients taking OTC omega-3 fatty 
acids should make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to Qualification 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Qualification 
unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to Qualification and dose and regimen expected to 
remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
Qualification and dose and regimen expected to remain constant during the treatment 
period 
f. Glybera gene therapy within 2 years prior to Qualification 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to Qualification and regular clinical monitoring 
is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to Qualification and dose and regimen expected to remain constant during the 
treatment period 
i. Plasma apheresis within 4 weeks prior to Qualification or planned during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to Qualification (Occasional 
or intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of Qualification or of > 499 mL within 
60 days of Qualification 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or 
placebo) 


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17. Have any other conditions, including new or worsening of existing condition, which, in 
the opinion of the Investigator or the Sponsor would make the patient unsuitable for 
inclusion, or could interfere with the patient participating in or completing the study 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification  
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 2.5, 
4, 6, 8, 10, 12, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 40, 42, 44, 46, 48, and 50 may be 
conducted by a home healthcare nurse.  Approval for study procedures to be conducted by a 
home healthcare nurse on other outpatient visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples and samples drawn locally should also 
be sent to the central laboratory for analysis whenever possible.  Every effort should be made to 
ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  Dosing 
instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.3 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 


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subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.4 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the at least 26-week 
post-treatment evaluation period or will participate in an expanded access program pending 
approval by the IRBs/IEC, and the appropriate regulatory authorities.  The 26-week period 
consists of at least 6 Study Center visits on Weeks 54, 56, 58, 65, 71, and 78 (Weeks 54, 56, 58, 
and 71 may be conducted by a home healthcare nurse), as outlined in the Schedule of Procedures 
in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1 week and determined not to have met a stopping rule before dosing 
can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to ensure that the count 
has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 


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6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 roll over patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, 
Week 65, and Week 78. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, Week 65, and Week 78. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, Week 65, and Week 78. 


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2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent† or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 


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For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
* Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are 
not acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2 °C to 8 °C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 


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7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 


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For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
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Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 2 in Section 8.6.3. 
Additional lab tests will be determined by the Sponsor Medical Monitor or designee in 
consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or 
clinically-relevant, non-major bleeding events (which are defined in Section 8.6.3), for example 
excess bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event 
occurs, the Investigator must notify the Sponsor Medical Monitor and additional testing of 
coagulation parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), 
INR and platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 


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symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as one in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 


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patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1 week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 


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• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 


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4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 2 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a rate of decline ≥ 50% between two 
consecutive assessments, irrespective of the platelet level, then dosing of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored daily until 
2 successive values show improvement then monitored every 2-3 days until platelet count is 
stable. 
Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note:  may require continuation with oral steroids after methylprednisolone).  In order to reduce 
the unlikely but potential increased risk of pancreatitis during the period of corticosteroid 
therapy, triglyceride levels will be monitored weekly during corticosteroid treatment and the 
laboratory alert will be changed from an increase of 2,000 to 500 mg/dL during that period. 


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In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks or a reduced dose of 150 mg per week (refer to Section 8.7).  The suitability of the 
patient for continued dosing will be determined by the Investigator in consultation with the Study 
Medical Monitor and will be based on factors such as the original rate of decline in the patient’s 
platelet count, whether any bleeding events were experienced by the patient, and the speed of 
recovery of platelet count upon holding of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Following a rechallenge platelet count should be tested every week until count is stable. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
 


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Table 2 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every 1 week until stable* 
75K-100K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 1 week 
50K-75K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 or a rate of 
decline ≥ 50% between 
two consecutive 
assessments, irrespective of 
the platelet level 
Permanently discontinue Study Drug   
Closer observation 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
< 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended** 
Consider need for hospitalization 
and referral to hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
At least 3 consecutive values measured weekly that are stable as determined by the Sponsor Medical Monitor 
and > 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methyl prednisolone).  In order 
to reduce the unlikely but potential increased risk of pancreatitis during the period of corticosteroid therapy, 
triglyceride levels will be monitored weekly during corticosteroid treatment and the laboratory alert will be 
changed from an increase of 2,000 to 500 mg/dL during that period. 
 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 2 (above). 


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Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 
schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in Table 2 in Section 8.6.3 for the first 6 weeks after 
discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3), the next platelet count should be taken within at least 6 weeks so that patients 
are monitored for at least 12 weeks after discontinuing Study Drug.  Patients should also be 
strongly encouraged to attend applicable landmark visits at Weeks 12, 13, 25, 26, and 50, 52 
(calculated based on the time elapsed since Day 1) to collect fasting lipid panels and conduct 
safety assessments in accordance with the Schedule of Procedures in Appendix A.  Any patient 
who discontinues treatment after Week 44 should also be strongly encouraged to attend a final 
follow-up visit (Week 78 visit assessments) approximately 26 weeks after their last dose of 
Study Drug, in addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 2 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 


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6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  
Patients should also be encouraged to undergo a final follow-up visit (Week 78, see Appendix A) 
prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 


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Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline Qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 78 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
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Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 3 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 


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A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 78 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 


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Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 78 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
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• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 


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9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
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9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active 
Study Drug and have a baseline TG assessment.  The FAS represents the practically-feasible 
intent-to-treat (ITT) population as delineated in ICH Guideline E9. 


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Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline will be the last non-missing assessment prior to the first dose of Study Drug.  Details 
will be provided in the SAP. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group of the index studies for 
patients on active Study Drug in the ISIS 304801-CS6 or ISIS 304801-CS16 index studies, and 
pooled treatment naïve group which includes patients on placebo in index studies.  Where 
appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided tests 
with 5% Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will 
be assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK 
endpoints will be assessed in the PK Set as applicable. 


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10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group and overall.  The patient disposition will be summarized by treatment group and 
overall.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
and overall. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term 
and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group.  Response rate of patients with fasting plasma TG 
< 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and 
Month 12 will be summarized.  Response analysis will also be conducted using a range of fasting 
plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group for other fasting lipid measures including non-HDL-C, apoB, 
HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 


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Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 
2 patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the 
index study will receive the first treatment of volanesorsen (single-dose PK), while patients who 
received volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these 
patients reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time 
taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under 
the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration 
(CL0-24h /F) will be calculated from CL0-24h /F = Actual Dose/AUC0-24h.  Mean residence time 
(MRT) from time zero to 24 hours after the SC administration will be calculated from the 
equation, MRT0-24h = AUMC0-24h /AUC0-24h, where AUMC0-24h is the area under the moment 
plasma concentration-time curve from time zero to 24 hours after the SC administration.  Other 
PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 
Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the last ADA sample 
collection day, and subject - peak titer if applicable, will be listed by their prior treatment in 
Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 


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positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by treatment group.  Furthermore, onset and titer of the ADA 
response, if applicable, will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., %change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 


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the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 


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12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 


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The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 


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13. 
REFERENCES 
Altmann KH, Fabbrot D, Dean NM, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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Protocol - France 
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66 
Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


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14. 
APPENDICES 
 
 
 


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Appendix A 
Schedule of Procedures 
 
Qualification through Treatment Period 
Post-Treatment Follow-up 
 


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Appendix A Schedule of Procedures – Qualification through Treatment Period 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to -1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to -7 1 
2 
11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
Xk 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
CBC with Differentialb 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Coagulation (aPTT, PT, INR) 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
Xn 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Plasma PK - Volanesorsen 
 
Xl 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
FSH (women only, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Archived Serum & Plasma 
Samplese 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Troponin Io 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A Schedule of Procedures - Qualification through Treatment Period Continued 
Study Period 
Quala 
Treatment Period 
Study Week 
-2 to -1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to -
7 
1 
2 11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Urinalysisc 
X 
Xm 
 
 
X 
 
X 
 
 
Xm 
 
Xm 
 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Genetic testing for FCS diagnosis (if 
not available in medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Food/Drink Diary (quarterly)h 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Diet/Alcohol Counselingi 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Appendix A Schedule of Procedures – Post-Treatment Follow-up  
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Informed Consent 
 
 
 
 
 
Outpatient Visit 
Xj 
Xj 
X 
Xj 
X 
Inclusion/Exclusion Criteria 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
Echocardiography 
 
 
 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialb 
X 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
Serum Pregnancy Testd 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplese 
 
 
X 
 
X 
Troponin Io 
 
 
 
 
 
 
 
 


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Appendix A Schedule of Procedures – Post-Treatment Follow-up Continued 
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 
540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Urinalysisc 
 
Xm 
Xm 
Xm 
Xm 
Fundus Photographyf 
 
 
 
 
 
Genetic testing for FCS diagnosis 
(if not available in medical 
history)g 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
73 
Appendix A Schedule of Procedures Continued 
a 
Qualification procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should 
be collected in parallel and analyzed locally. In the event that both the central and local sample are unreportable 
(e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 1 week and 
determined not to have met a stopping rule before dosing can continue.  If there is no reportable platelet count 
within 14 days of the last platelet count, the Investigator will contact the patient to hold dosing until a new platelet 
count is obtained and reviewed.  All platelet count results will be promptly reviewed by the Investigator to ensure 
that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3.  In the event of any platelet count less than 
50,000/mm3 or a rate of decline ≥ 50% between two consecutive assessments, irrespective of the platelet level, 
then dosing of a patient with Study Drug (ISIS 304801 or placebo) will be stopped permanently.  Any case of a 
platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  
During treatment period urine and blood samples will be collected prior to Study Drug administration.  Does not 
apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or 
adverse events (e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of 
kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug 
(Group 2 ISIS 304801-CS16 roll over patients) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
g 
Genetic testing can be conducted for study Qualification (Group 2 ISIS 304801-CS16 roll over patients); genetic 
testing will only be conducted if allowed in the geographic region and only after the patient has given specific 
written informed consent for genetic testing 
h 
In addition to diary, patients will be contacted at random times during the study to review their current eating and 
drinking habits 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will 
also be performed by dietician or study personnel 
j 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as 
arranged by the Study Center personnel 
k 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
l 
Full or abbreviated PK profile (see Appendix C) 
m 
Expanded urinalysis (see Appendix B) 
n 
HbA1c only 
o 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
p 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until 
apoC-III levels return to baseline values 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
74 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
75 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
76 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
77 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose Pre-dose Pre-dose Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
Post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
78 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
79 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
80 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 7 
Protocol - France 
3 February 2017 
 
81 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
Adverse Event 
Mild 
Moderate 
Severe 
Urine 
Proteinuria 
Adults 
1 + proteinuria; 
2+ proteinuria; 
Urinary protein 
g/24 hrs; 
urinary protein < 1.0 g/24 hrs 
urinary protein 1.0 - 3.4 g/24 hrs; 
Children 
-
Urine PIC (Protein/Creatinine) 
Urine P/C >1.9 
ratio 0.5 - 1.9 
Gross hematuria; transfusion, 
Asymptomatic; clinical or diagnostic 
IV medications or 
Symptomatic; urinary catheter or hospitalization indicated; 
Hematuria 
observations only; intervention not 
bladder irrigation indicated 
elective endoscopic, radiologic 
indicated 
or operative intervention 
indicated 
tGrading for this parameter is derived from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept 2007 
*Grading for this parameter is derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, Nov 2014 
tModified for consistency with the ADA and Endocrine Society Guidelines (Seaquist ER, Anderson J, Childs B, et al. 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. 
Diabetes Care 2013;36: 1384-95) 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 6 - Netherlands – 11 April 2017 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 30480 I-CS7 
Protocol - Netherlands 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 6 
11 April 2017 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 6 - Netherlands - 11 April 2017 
Protocol History: 
Original Protocol: 
Protocol Amendment 1: 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Protocol Amendment 5: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
MD, MBA 
28 August 2015 
2 February 2016 
22 April 2016 
9 May 2016 
6 June 2016 
6 July 2016 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
3
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 6 - Netherlands 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801)
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
, Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
11 April 2017 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 6 Netherlands 
Date: 
11 April 2017 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 11 April 2017, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.................................................................................................... 10 
PROTOCOL SYNOPSIS ........................................................................................................... 28 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 32 
STUDY GLOSSARY .................................................................................................................. 33 
1. 
OBJECTIVES ................................................................................................................. 35 
2. 
BACKGROUND AND RATIONALE .......................................................................... 35 
2.1 
Overview of Disease ......................................................................................................35 
2.2 
Therapeutic Rationale ....................................................................................................36 
2.3 
Volanesorsen ..................................................................................................................37 
2.3.1 
Mechanism of Action .............................................................................................37 
2.3.2 
Chemistry ...............................................................................................................38 
2.3.3 
Preclinical Experience ............................................................................................39 
2.3.4 
Clinical Experience ................................................................................................40 
2.4 
Rationale for Dose and Schedule of Administration .....................................................41 
3. 
EXPERIMENTAL PLAN .............................................................................................. 42 
3.1 
Study Design ..................................................................................................................42 
3.2 
Number of Study Centers ..............................................................................................42 
3.3 
Number of Patients ........................................................................................................42 
3.4 
Overall Study Duration and Follow-up .........................................................................42 
3.4.1 
Qualification ...........................................................................................................42 
3.4.2 
Treatment ................................................................................................................42 
3.4.3 
Post-Treatment .......................................................................................................42 
3.5 
End-of-Study ..................................................................................................................42 
3.6 
Data and Safety Monitoring Board ................................................................................43 
4. 
PATIENT ENROLLMENT ........................................................................................... 43 
4.1 
Qualification ..................................................................................................................43 
4.2 
Enrollment .....................................................................................................................43 
5. 
PATIENT ELIGIBILITY .............................................................................................. 43 
5.1 
Inclusion Criteria ...........................................................................................................43 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-CS16) 
Index Study Roll-over Patients ......................................................................................44 
6. 
STUDY PROCEDURES ................................................................................................ 45 
6.1 
Study Schedule ..............................................................................................................45 
6.1.1 
Qualification ...........................................................................................................45 
6.1.2 
Treatment Period ....................................................................................................45 
6.1.3 
Extended Treatment Period ....................................................................................45 
6.1.4 
Pharmacokinetic (PK) Subgroup ............................................................................46 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
6 
6.1.5 
Post-Treatment Period ............................................................................................46 
6.2 
Additional Study Assessments .......................................................................................47 
6.2.1 
Laboratory Assessments .........................................................................................47 
6.2.2 
Physical Exams and Vital Signs .............................................................................47 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................47 
6.2.2.2 
Lipemia Retinalis .............................................................................................47 
6.2.3 
Echocardiography ...................................................................................................47 
6.2.4 
ECG ........................................................................................................................48 
6.2.5 
MRI ........................................................................................................................48 
6.2.6 
Quality of Life Assessments ...................................................................................48 
6.2.7 
Disease Symptom Diary .........................................................................................48 
6.2.8 
Diet Monitoring ......................................................................................................48 
6.2.9 
Family History ........................................................................................................48 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) ..48 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................49 
6.3.1 
Contraception Requirements ..................................................................................49 
6.3.2 
Other Requirements ................................................................................................50 
7. 
STUDY DRUG ................................................................................................................ 50 
7.1 
Volanesorsen Description ..............................................................................................50 
7.2 
Packaging and Labeling .................................................................................................50 
7.3 
Study Drug Accountability ............................................................................................50 
8. 
TREATMENT OF PATIENTS ..................................................................................... 51 
8.1 
Volanesorsen Administration ........................................................................................51 
8.2 
Other Protocol-Required Drugs .....................................................................................51 
8.3 
Other Protocol-Required Treatment Procedures ............................................................51 
8.4 
Treatment Precautions ...................................................................................................51 
8.5 
Safety Monitoring Rules ................................................................................................51 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................52 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................53 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................55 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................55 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................55 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........55 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................56 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................56 
8.5.9 
Acute Pancreatitis ...................................................................................................57 
8.6 
Stopping Rules ...............................................................................................................57 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................58 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................58 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................58 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
7 
8.7 
Adjustment of Dose Frequency .....................................................................................61 
8.8 
Discontinuation of Study Treatment ..............................................................................61 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................61 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .62 
8.9 
Withdrawal of Patients from the Study ..........................................................................62 
8.10 
Concomitant Therapy and Procedures ...........................................................................62 
8.10.1 
Concomitant Therapy .............................................................................................63 
8.10.2 
Concomitant Procedures .........................................................................................63 
8.11 
Treatment Compliance ...................................................................................................63 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 64 
9.1 
Sponsor Review of Safety Information .........................................................................64 
9.2 
Regulatory Requirements ..............................................................................................64 
9.3 
Definitions .....................................................................................................................65 
9.3.1 
Adverse Event ........................................................................................................65 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................65 
9.3.3 
Serious Adverse Event (SAE) ................................................................................65 
9.4 
Monitoring and Recording Adverse Events ...................................................................66 
9.4.1 
Serious Adverse Events ..........................................................................................66 
9.4.2 
Non-Serious Adverse Events ..................................................................................66 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................66 
9.4.3.1 
Relationship to the Study Drug ........................................................................66 
9.4.3.2 
Severity ............................................................................................................67 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................67 
9.4.3.4 
Treatment Given for Adverse Event ................................................................67 
9.4.3.5 
Outcome of the Adverse Event ........................................................................67 
9.4.4 
Adjudication Committees .......................................................................................68 
9.5 
Procedures for Handling Special Situations ..................................................................68 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................68 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............69 
9.5.3 
Dosing Errors .........................................................................................................69 
9.5.4 
Contraception and Pregnancy .................................................................................69 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 70 
10.1 
Study Endpoints .............................................................................................................70 
10.1.1 
Efficacy Endpoints .................................................................................................70 
10.1.2 
Safety Endpoints .....................................................................................................70 
10.2 
Sample Size ....................................................................................................................71 
10.3 
Populations .....................................................................................................................71 
10.4 
Definition of Baseline ....................................................................................................71 
10.5 
Interim Analysis .............................................................................................................71 
10.6 
Planned Methods of Analysis ........................................................................................72 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
8 
10.6.1 
Demographic and Baseline Characteristics ............................................................72 
10.6.2 
Safety Analysis .......................................................................................................72 
10.6.3 
Efficacy Analysis ...................................................................................................73 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................73 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................73 
10.6.4.2 
Immunogenicity Analysis ................................................................................74 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 74 
11.1 
Informed Consent ..........................................................................................................74 
11.2 
Ethical Conduct of the Study .........................................................................................75 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................75 
11.4 
Patient Confidentiality ...................................................................................................75 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 76 
12.1 
Protocol Amendments ....................................................................................................76 
12.2 
Study Termination .........................................................................................................76 
12.3 
Study Documentation and Storage ................................................................................76 
12.4 
Study Monitoring ...........................................................................................................77 
12.5 
Language ........................................................................................................................77 
12.6 
Compensation for Injury ................................................................................................77 
13. 
REFERENCES ................................................................................................................ 78 
14. 
APPENDICES ................................................................................................................. 80 
Appendix A 
Schedule of Procedures ....................................................................................81 
Appendix B 
List of Laboratory Analytes .............................................................................87 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................89 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......91 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics .........................................................50 
Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the 
Lower Limit of Normal (x2) or < 100,000/mm3 (x1)* ..........................................54 
Table 3 
Actions in Patients with Low Platelet Count or Drop in Platelet Count ................60 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence ...................................................................................64 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
9 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms ...............36 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ....................................38 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen ...............40 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
10 
PROTOCOL AMENDMENT 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously 
to Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment Number: 
Amendment Date: 
6 - Netherlands 
11 April 2017 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 5 dated 6 July 2016: 
1. To update the platelet safety monitoring rules shown in Table 3.
2. To exclude enrollment of FCS patients in this open-label study who did not participate in
the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.
3. To add post heparin plasma LPL activity of ≤ 20% of normal in medical history as an
inclusion criteria for ISIS 304801-CS16 (Group 2) patients as has been allowed for
ISIS 304801-CS6 (Group 1) patients.
4. To allow patients who complete the 52-week treatment period to participate in an
expanded access program or continue dosing for up to an additional 52 weeks until an
expanded access program is approved and available in their country.  Patients not
participating in an expanded access program will enter the 13-week post-treatment
evaluation period.
5. Added archive blood sample for potential gene sequencing related to
hypertriglyceridemia (Group 2 if not available from index study).
6. Added:  Troponin I, platelet bound autoantibody testing at baseline (may be done), and
Table 2 Labs to be performed in the event of a platelet count Less than the Lower Limit
of Normal (x2) or < 100,000/mm3 (x1) to provided added patient safety; blood viscosity
(may be done) to assess potential benefit of ISIS 304801 administration; and platelet
aggregation (may be done) to assess platelet function.
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol, additions are 
indicated as underline and deletions are indicated as strikethrough: 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
11 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Section 3.1 
Study Design 
 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 
or ISIS 304801-CS16 index studies 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment 
and follow-up period.  Following the Week 52 visit, patients will have the 
option of participating in an expanded access program or continuing 
dosing for up to an additional 52 weeks until an expanded access program 
is approved and available in their country.  Patients not participating in an 
expanded access program will enter a 13-week post-treatment evaluation 
period 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
Synopsis 
Section 5.1 
Inclusion 
Criteria 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, 
per Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients who enrolled in ISIS 304801-CS16 must 
also meet the following criteria in order to enter into the open-label 
study: 
 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at ScreeningQualification for 
the ISIS 304801-CS16 index study Group 3:  Fasting TG ≥ 750 
mg/dL at Screeningfor this open-label study 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
Synopsis 
Section 5.1 
Inclusion 
Criteria 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of 
the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal in medical 
history. Note: testing of LPL activity should not be performed to 
confirm eligibility for the study 
To add LPL activity 
of ≤ 20% of normal 
in medical history 
as an inclusion 
criteria for Group 2 
patients as has 
been allowed for 
Group 1 patients. 
Synopsis 
Section 5.2 
Exclusion 
Criteria 
Exclusion Criteria for Group 3 (patients who did not participate in an 
index study) 
1. 
Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in 
dosage or addition of new medication within 12 weeks of screening 
[with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to screening 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
 
 
 


ISIS 304801-CS7 
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11 April 2017 
 
12 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Section 5.2 
Exclusion 
Criteria 
Continued 
4. History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive 
cardiac failure requiring a change in medication or major surgery within 
3 months of screening 
5. Any of the following laboratory values at Screening 
a. Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be  
≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine protein 
measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or CKD-
EPI formulas can be used instead of Cockcroft-Gault for 
estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Screening 
d. 
LDL-C > 130 mg/dL at Screening 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. 
Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. 
History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
8. 
History of heart failure with NYHA greater than Class II 
9. 
Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus 
(HIV), hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1-month of screening, or 5 half-lives of investigational agent, 
whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
13 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Section 5.2 
Exclusion 
Criteria 
Continued 
14. Use of any of the following: 
a. 
Statins, omega-3 fatty acids (prescription and OTC), or fibrates 
unless on a stable dose for at least 3 months prior to screening 
and dose and regimen expected to remain constant during the 
treatment period.  Patients taking OTC omega-3 fatty acids should 
make every effort to remain on the same brand throughout the 
study 
b. 
Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
screening 
c. 
Systemic corticosteroids or anabolic steroids within 6 weeks prior 
to screening unless approved by the Sponsor Medical Monitor 
d. 
Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to screening 
and dose and regimen expected to remain stable throughout the 
study 
e. 
Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to screening and dose and regimen expected to 
remain constant during the treatment period 
f. 
Glybera gene therapy within 2 years prior to screening 
g. 
Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening and regular clinical monitoring is performed 
h. 
Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening and dose and regimen expected 
to remain constant during the treatment period 
i. 
Plasma apheresis within 4 weeks prior to screening or planned 
during the study 
j. 
Prior exposure to ISIS 304801 
k. 
Any other medication unless stable at least 4 weeks prior to 
screening (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of 
> 499 mL within 60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or 
the Sponsor would make the patient unsuitable for inclusion, or could 
interfere with the patient participating in or completing the study 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
14 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Study Design 
and Treatment 
Schema 
Section 3.1 
Study Design 
Section 3.4.1 
Qualification 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up to 
2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A 
• 
Group 3 patients (did not participate in an index study):  An up to 
8-week screening and qualification period, including a diet stabilization 
period of at least 6 weeks (screening and diet stabilization period may 
be reduced, per Sponsor approval, if the patient is following a diet for 
optimal control of TGs and disease management prior to screening).  
Please refer to Section 6.1.2 and Appendix A 
• 
All patients: 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
Option to participate in an extended treatment period (up to an 
additional 52 weeks) 
o 
A 13-week post-treatment evaluation period or expanded access 
program 
The patients, Investigators, study staff, and the Sponsor will remain blinded 
to lipid data through the last patient’s Week 13 visit of the open-label study 
or until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, blood 
viscosity, volanesorsen plasma concentrations, immunogenicity (IM) 
testing, platelet aggregation, liver/spleen magnetic resonance imaging 
(MRI), ECGs, echocardiograms and quality of life assessments will be 
performed according to the schedule of procedures in Appendix A.  Dietary 
counseling will be repeated at intervals throughout the treatment and follow-
up period and a daily food/drink diary will be completed for the week prior to 
each quarterly visit by each patient.  Following the Week 52 visit, patients 
will have the option of participating in an expanded access program or 
continuing dosing for up to an additional 52 weeks until an expanded 
access program is approved and available in their country.  Patients not 
participating in an expanded access program will enter the 13-week 
post-treatment evaluation period. 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
 
To allow patients 
who complete the 
52-week treatment 
period to participate 
in an expanded 
access program or 
continue dosing for 
up to an additional 
52 weeks until an 
expanded access 
program is 
approved and 
available in their 
country. 
 
Section 3.4.3 
Post-
Treatment 
The post-treatment evaluation period is 13 weeks and consists of 27 Study 
Center visits on Weeks 53, 54, 55, 56, 57, 58, and 65 (Weeks 53, 54, 55, 
56, 57, and 58 may be conducted by a home healthcare nurse). 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
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Protocol - Netherlands 
11 April 2017 
 
15 
Protocol 
Section 
Description of Change 
Rationale 
Section 4.1 
Qualification 
Group 3 (Screening and Qualification):  At the time of consent, the patient 
will be considered enrolled into the study and will be assigned a unique 
screening number before any study procedures, including screening 
procedures, are performed.  At the time of enrollment, patients will be 
assigned a unique patient identification number.  This number will be used 
to identify the patient throughout the trial and must be used on all study 
documentation related to that patient.  The screening number and patient 
identification number must remain constant throughout the entire trial.  In 
the event the patient is re-consented and re-screened the patient must be 
given a new screening number.  Screening numbers and patient 
identification numbers, once assigned, will not be re-used. 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
Section 6.1 
Study 
Schedule 
6.1.2 Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, patients 
must sign and date the informed consent form.  An 8-week period, including 
a diet stabilization period of at least 6 weeks (screening and diet 
stabilization period may be reduced, per Sponsor approval, if the patient is 
following a diet for optimal control of TGs and disease management prior to 
screening) is given to perform the screening evaluations.  The qualification 
assessments will be performed at Week -2 to -1, ideally after patient 
eligibility has been determined, and on Study Day 1.  Abnormal screening 
results may be retested for review by the Study Medical Monitor for 
eligibility purposes 
To exclude 
enrollment of FCS 
patients in this 
open-label study 
who did not 
participate in the 
ISIS 304801-CS6 or 
ISIS 304801-CS16 
index studies. 
Section 6.1.2 
Treatment 
Period 
During the treatment period, patients will report to the study center for clinic 
visits a minimum of 5 times during Weeks 1-52 (see Schedule of 
Procedures in Appendix A).  Study Drug will be administered once weekly 
unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory 
parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, blood viscosity, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, platelet 
aggregation, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in 
Appendix A.  Adverse events at the injection site should be collected as 
adverse events.  Dietary counseling will be reinforced at intervals 
throughout the treatment and follow-up period and all patients will complete 
a daily food diary for one week prior to their quarterly visit.  All blood and 
urine samples should be collected prior to volanesorsen administration.  
Blood sampling at Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 
19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 
41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 5051 may be conducted by a 
home healthcare nurse.  Approval for study procedures to be conducted by 
a home healthcare nurse on other outpatient visit days will require prior 
approval by the Sponsor.  Patients must be fasted prior to drawing all blood 
samples and samples drawn locally should also be sent to the central 
laboratory for analysis whenever possible.  Every effort should be made to 
ensure the previous week’s dose is given 7 days prior to a scheduled clinic 
visit.  Dosing instructions and training will be provided to the patient where 
applicable. 
To provide added 
patient safety 
regarding platelet 
count reductions 
and ISIS 304801 
dose exposure. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
16 
Protocol 
Section 
Description of Change 
Rationale 
Section 6.1.3 
Extended 
Treatment 
Period 
6.1.3 Extended Treatment Period 
Patients will have the option of continuing dosing for up to an additional 
52 weeks until an expanded access program is approved and available in 
their country. 
During the extended treatment period, patients will report to the study center 
for clinic visits during Weeks 54-104 (see Schedule of Procedures in 
Appendix A).  Study Drug will be administered once weekly unless the patient 
is on a biweekly dosing schedule for safety reasons (Section 8.1).  Collection 
and measurement of vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, volanesorsen plasma 
concentrations, IM testing, ECGs, and physical examinations will be 
performed according to the Schedule of Procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary 
counseling will be reinforced at intervals throughout the extended treatment 
period.  All blood and urine samples should be collected prior to 
volanesorsen administration.  Blood sampling at Weeks 53, 54, 55, 56, 57, 
58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 79, 
80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 
101, 102, and 103 may be conducted by a home healthcare nurse.  Approval 
for study procedures to be conducted by a home healthcare nurse on other 
outpatient visit days will require prior approval by the Sponsor.  Patients must 
be fasted prior to drawing all blood samples and samples drawn locally 
should also be sent to the central laboratory for analysis whenever possible.  
Dosing instructions and training will be provided to the patient where 
applicable. 
To allow patients 
who complete the 
52-week treatment 
period to participate 
in an expanded 
access program or 
continue dosing for 
up to an additional 
52 weeks until an 
expanded access 
program is approved 
and available in their 
country. 
 
Section 6.1.5 
Post-Treatment 
Period 
After completion of the Week 52 visit assessments, patients will have the 
option of participating in an expanded access program or continuing dosing 
for up to an additional 52 weeks until an expanded access program is 
approved and available in their country as described in Section 6.1.4.  
Patients not participating in an expanded access program will enter the 
13-week post-treatment evaluation period.  This 13-week post-treatment 
evaluation period consists of 4 7 Study Center visits on Weeks 53, 54, 55, 56, 
57, and 58 (which may be conducted by a home healthcare nurse), and 
Week 65 as outlined in the Schedule of Procedures in Appendix A.  Patients 
who complete, or terminate early from, the extended treatment period without 
subsequently participating in an expanded access program will enter a 
13-week post-treatment evaluation period consisting of 7 Study Center visits 
on Weeks 105, 106, 107, 108, 109, and 110 (which may be conducted by a 
home healthcare nurse), and Week 117 as outlined in the Schedule of 
Procedures in Appendix A. 
To allow patients 
who complete the 
52-week treatment 
period to participate 
in an expanded 
access program or 
continue dosing for 
up to an additional 
52 weeks until an 
expanded access 
program is approved 
and available in their 
country. 
 
To provide added 
patient safety 
regarding platelet 
count reductions and 
ISIS 304801 dose 
exposure. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
17 
Protocol 
Section 
Description of Change 
Rationale 
Section 6.2.1 
Laboratory 
Assessments 
Each time a hematology lab is drawn and sent to the central laboratory for 
analysis an additional sample should be collected in parallel and analyzed 
locally.  In the event that both the central and local sample are unreportable 
(e.g., due to hemolyzed or clumped blood samples) another sample must be 
repeated within 1-week and determined not to have met a stopping rulethe 
result must be reviewed by the Investigator and confirmed to be acceptable 
before dosing can continue.   
If there is no reportable platelet count within 14 days of the last platelet count, 
the Investigator will contact the patient to hold dosing until a new platelet 
count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to 
ensure thatdetermine if the count has not met thea stopping rule, or the dose 
reduction rule and to determine whether the rate of decline is suggestive that 
the patient could be approachingof 100,000/mm3, or the dose pause rule of 
75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an 
expedited fashion to the Sponsor. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
Section 6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine 
position for at least 5 minutes.  ECGs will be performed in triplicate at 
Week 13, Week 26, Week 38, Week 52, and Week 65.  Patients in the 
Extended Treatment Period will have ECGs performed in triplicate at 
Week 76 and Week 104. 
To provide patient 
safety during the 
Extended Treatment 
Period. 
Section 6.2.8 
Diet Monitoring 
2. Patients will receive diet/alcohol counseling by qualified study personnel 
at clinic visits throughout the course of the study.  Qualified study 
personnel will telephone the patient to provide diet/alcohol counseling for 
visits that are conducted by a clinical service.  Patients in the Extended 
Treatment Period will receive diet/alcohol counseling by qualified study 
personnel at clinic visits only. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during 
clinic visits, telephone calls from a dietitian or qualified study personnel to 
assess as to how each patient is maintaining their diet will may be 
conducted randomly during the treatment and post treatment follow-up 
periods. 
To provide 
diet/alcohol 
counseling during 
the Extended 
Treatment Period. 
Section 6.2.10 
Chart Review 
for Incidents of 
Acute 
Pancreatitis in 
Medical 
History 
(Group 2) 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History 
(Group 2) 
Patient records will be reviewed for incidents of acute pancreatitis occurring 
up to 5 years prior to Qualification and information relating to these events 
will be collected for independent adjudication. 
To assess acute 
pancreatitis in 
medical history in 
Group 2 patients. 
Section 8.1 
Volanesorsen 
Administration 
Every effort should be made to ensure the previous week’s dose is given 7 
days prior to a scheduled clinic visit. 
Dosing 
recommendations 
provided in updated 
monitoring and drug 
administration 
updates. 
 
 


ISIS 304801-CS7 
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11 April 2017 
 
18 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.5.2 
Safety 
Monitoring for 
Platelet Count 
Results 
Actions to be taken in the event of reduced platelet count are shown in 
Table 23 in Section 8.6.3.  
Monitor every 1 week unless otherwise specified. 
Study Drug administration is contingent on the availability of the 
immediately preceding test result.  An interpretable platelet value must be 
available within 7 days prior to dosing.  Only the study doctor or qualified 
designee can authorize continued Study Drug administration based on an 
acceptable platelet value.  Patients should not administer a dose until they 
have been contacted by their study doctor or designee and told that it is 
acceptable to dose.  Authorization to dose must be documented in the 
patient’s medical records. 
Due to the 1 to 2-year study duration it is anticipated that patients may 
undertake travel including vacations, which may impede weekly platelet 
monitoring.  In some situations, it may be possible to arrange for local 
laboratory testing or use of the home healthcare service at their temporary 
location.  The intent is to maintain weekly platelet monitoring and dosing 
where possible, as well as Investigator site contact with the study patients.  
However, if the above options are not possible, a temporary interruption of 
study treatment will be planned with a prompt blood draw upon the 
patient’s return which must be reported and reviewed by the Investigator 
prior to the patient resuming dosing. 
The tests outlined in Table 2 should also be performed as soon as 
possible.  Additional lab tests will be determined by the Sponsor Medical 
Monitor or designee in consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an 
expedited fashion to the Sponsor (See also Stopping Rules Section 8.6.3). 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
19 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.5.2 
Safety 
Monitoring for 
Platelet Count 
Results 
Continued 
Added Table 2: 
Table 2 Labs to Be Performed in the Event of a Platelet Count Less than 
the Lower Limit of Normal (x2) or < 100,000/mm3 (x1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) 
of platelet count less than the lower limit of normal or who have any 
1 occurrence of platelets < 100,000/mm3.  Labs only need to be performed 
once.  Labs may be collected over multiple visits, if blood requirements are 
a concern, as per investigator discretion. 
Note: 
The following labs may change as additional data is assessed, 
and sites will be updated regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to 
central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for Qualification) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
20 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Actions to be taken in the event of a low platelet count are summarized in 
Table 23 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with 
major bleeding or clinically-relevant non-major bleeding (defined below; 
Schulman et al. 2005), dosing of a patient with volanesorsen will be stopped 
permanently.  The follow-up schedule for any events meeting this stopping 
criterion will be determined by the Investigator in consultation with the 
Sponsor Medical Monitor.  
In the event of any platelet count less than 2550,000/mm3, or a platelet count 
less than 75,000/mm3 that occurs while the patient is on dosing at 300 mg 
every 2 weeks or 150 mg every week then dosing of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored 
as outlined in Table 3. daily until 2 successive values show improvement 
then monitored every 2-3 days until platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count 
is less than 2550,000/mm3.  Recovery in platelet count may be accelerated 
by administration of high dose steroids.  Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg 
daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5 2 mg/kg/d 
for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone).  
Triglyceride levels be monitored weekly, and AE monitoring will continue, 
during corticosteroid treatment and the laboratory alert will be changed from 
an increase of 2,000 to 500 mg/dL during that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of 
major bleeding or clinically-relevant non-major bleeding (defined below; 
Schulman et al. 2005), dosing of a patient with volanesorsen should be 
suspended temporarily until the platelet count has recovered to 
> 100,000/mm3.  If dosing is continued it should be at a reduced dose 
frequency of 300 mg every 2 weeks or a reduced dose of 150 mg per week 
(refer to Section 8.7).  The suitability of the patient for continued dosing will 
be determined by the Investigator in consultation with the Study Medical 
Monitor and will be based on factors such as the original rate of decline in 
the patient’s platelet count, whether any bleeding events were experienced 
by the patient, and the speed of recovery of platelet count upon holding of 
dosing. 
If after the first dosing rechallenge the platelet count again falls below 
75,000/mm3, then dosing of the patient with Study Drug will be stopped 
permanently. 
Following a rechallenge platelet count should be tested every week until 
count is stable. 
Any unreportable platelet count result must be rechecked and determined 
not to have met a stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet 
count, the Investigator will contact the patient to hold dosing until a new 
platelet count is obtained and reviewed. 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
21 
Protocol 
Section 
Description of Change 
Rationale 
Section 
8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Continued 
Was: 
Table 2 Actions in Patients with Low Platelet Count  
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
Normal range, 
> 140K/mm3 
No action 
Monitor every 2 weeks 
100K-
140K/mm3 
No action 
Closer observation 
Monitor every 1 week until 
stable* 
75K-
100K/mm3 
Permanently reduce 
dose frequency to 300 
mg every 2 weeks or 
reduce dose to 150 mg 
weekly 
Closer observation 
Monitor every 1 week 
50K-75K/mm3 
If occurs while on dose 
of 300 mg every 
2 weeks or 150 mg 
every week then 
permanently 
discontinue Study Drug, 
otherwise dose pause. 
When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 
If occurs while on dose 
of 300 mg every 
2 weeks or 150 mg 
every week then 
permanently 
discontinue Study Drug, 
otherwise dose pause. 
When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor  
Closer observation 
Monitor daily until 
2 successive values show 
improvement then monitor 
every 2-3 days until platelet 
count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count < 50K/mm3 if possible 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
22 
Protocol 
Section 
Description of Change 
Rationale 
Section 
8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Continued 
Table 2 Actions in Patients with Low Platelet Count Continued 
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
< 25K/mm3 
Permanently 
discontinue 
Study Drug 
Closer observation: 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended** 
Consider need for 
hospitalization and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
At least 3 consecutive values measured weekly that are stable as 
determined by the Sponsor Medical Monitor and > 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration of high 
dose steroids.  Treatment guidelines for immune thrombocytopenia 
(Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days 
every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 
2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days 
(note:  may require continuation with oral steroids after methyl 
prednisolone) 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
23 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Continued 
Is: 
 
Table 3 Actions in Patients with Low Platelet Count or Drop in Platelet 
Count 
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
 
Study Drug administration 
is contingent on the 
availability of the 
immediately preceding 
test result.  An 
interpretable platelet 
value must be available 
within 7 days prior to 
dosing.  Only the study 
doctor or qualified 
designee can authorize 
continued Study Drug 
administration based on 
an acceptable platelet 
value.  Patients should 
not administer a dose 
until they have been 
contacted by their study 
doctor or designee and 
told that it is acceptable to 
dose.  Authorization to 
dose must be 
documented in the 
patient’s medical records. 
Monitor every 1 week 
unless otherwise 
specified 
Obtain additional lab tests 
(Table 2) if 2 occurrences 
consecutive or non-
consecutive) of platelet 
count 140K - > 100K/mm3 
or 1 occurrence of platelet 
count ≤ 100K/mm3.  Labs 
only need to be performed 
once.  Labs may be 
collected over multiple 
visits, if blood requirements 
are a concern, as per 
Investigator discretion. 
> 100K/mm3 
Weekly 300 mg Study 
Drug administration 
100K/mm3 - 
> 75K/mm3 
Permanently reduce dose 
frequency to 300 mg 
every 2 weeks 
 
75K/mm3 - 
> 50K/mm3 
• If occurs while on dose 
of 300 mg every 
2 weeks then 
permanently 
discontinue Study Drug, 
otherwise dose pause 
• When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks only if 
approved by Sponsor 
Medical Monitor 
• 
Monitor every 2-3 days 
until 2 successive 
values are >75K/mm3 
then monitor every 
1 week 
• 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/ 
anticoagulant 
medication 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
24 
Protocol 
Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping 
Rules for 
Platelet 
Count 
Results 
Continued 
Table 3 Actions in Patients with Low Platelet Count or Drop in Platelet 
Count Continued 
Platelet 
Count on Rx 
Drug Dose 
Monitoring 
≤ 50K/mm3 
Permanently discontinue 
Study Drug 
• Monitor daily until 
2 successive values 
show improvement then 
monitor every 2-3 days 
until 2 successive values 
are > 75K/mm3 then 
monitor every 1 week 
• Patient should be 
evaluated by a 
hematologist to provide 
diagnostic and 
therapeutic management 
• Steroids recommended*.  
It is strongly 
recommended that, 
unless the patient has a 
medical contraindication 
to receiving 
glucocorticoids, the 
patient receives 
glucocorticoid therapy to 
reverse the platelet 
decline.   
• Monitor triglyceride levels 
weekly and continue AE 
monitoring during steroid 
therapy 
• Discontinue antiplatelet 
agents/ NSAIDS/ 
anticoagulant medication 
while platelet count 
is< 50K/mm3 if possible 
* 
Recovery in platelet count may be accelerated by administration of high 
dose steroids.  Treatment guidelines for immune thrombocytopenia 
(Provan et al. 2010) recommend dexamethasone 40 mg daily for 4 days 
every 2-4 weeks for 1-4 cycles; prednis(ol)one 0.5-2 mg/kg/d for 
2-4 weeks then taper; or methylprednisolone 30 mg/kg/day for 7 days 
(note:  may require continuation with oral steroids after 
methylprednisolone) 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
25 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Section 
10.1.1 
Efficacy 
Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the 
treatment period 
• Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-HDL-C, apoB, HDL-C, 
apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Change in blood viscosity (may be evaluated) 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
Blood viscosity 
added to assess 
potential benefit 
of ISIS 304801 
administration. 
 
Synopsis 
Section 
10.1.2 Safety 
Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
• Platelet aggregation (may be evaluated) 
Platelet 
aggregation 
added to assess 
platelet function 
following 
ISIS 304801 
administration. 
Section 10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 
1 dose of active Study Drug and have a baseline TG assessment.  The FAS 
represents the practically-feasible intent-to-treat (ITT) population as 
delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 
13 scheduled doses of volanesorsen and with no significant protocol 
deviations that would be expected to affect efficacy and PD assessments.  
The detailed criteria will be specified and finalized prior to the final database 
lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of 
volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of 
volanesorsen, and have at least 1 evaluable post first dose PK sample 
collected, analyzed, and reported. 
Modified to 
include, in the 
FAS, only those 
patients that are 
randomized and 
dosed and have a 
baseline TG 
assessment and 
clarified the PK 
Population. 
Section 10.4 
Definition of 
Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in 
Groups 1 and 2:  Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-
CS16) index study baseline and the baseline in this open-label study, which 
is defined as the average of Day 1 pre-dose assessment and the last 
measurement prior to Day 1 (e.g., qualification assessments or assessments 
from final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if 
used for qualification).  For Group 3 patients, the baseline for fasting lipid 
measurements is defined as the average of Day 1 pre-dose assessment and 
the last measurement prior to Day 1 in this open-label study. 
For other measurements, baseline for patients on active treatment in the 
ISIS 304801-CS6 or ISIS 304801-CS16 index study will be the ISIS 304801-
CS6 or ISIS 304801-CS16 index study baseline.  For patients on placebo in 
the ISIS 304801-CS6 or ISIS 304801-CS16 index study and Group 3 
patients, baseline will be the last non-missing assessment prior to the first 
dose of Study Drug. 
To exclude 
enrollment of 
FCS patients in 
this open-label 
study who did not 
participate in the 
ISIS 304801-CS6 
or ISIS 304801-
CS16 index 
studies. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
26 
Protocol 
Section 
Description of Change 
Rationale 
Appendix A 
Removed Screening period (Group 3) 
Removed Week 2.5 
 
Added:  Medical History 
b 
Patient charts will be reviewed in order to collect data for events of 
acute pancreatitis or suspected pancreatitis in the patient’s medical 
history.  Chart review may be conducted at any time during the study.  
These events will be adjudicated in the same manner as for events of 
pancreatitis during the study 
 
CBC with Differential 
c 
Each time a hematology lab is drawn and sent to the central laboratory 
for analysis an additional sample should be collected in parallel and 
analyzed locally.  In the event that both the central and local sample are 
unreportable (e.g., due to hemolyzed or clumped blood samples) 
another sample must be repeated within 1 week and the result must be 
reviewed by the Investigator and confirmed to be acceptable and 
determined not to have met a stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet 
count, the Investigator will contact the patient to hold dosing until a new 
platelet count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that determine if the 
count has not met the a stopping rule, and to determine whether the 
rate of decline is suggestive that the patient could be approaching the 
or the dose reduction rule of 100,000/mm3, or the dose pause rule of 
75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be 
reported in an expedited fashion to the Sponsor 
 
Added:  Troponin I 
 
Added:  Blood Viscosity, Platelet Aggregation, Platelet Bound 
Autoantibodies 
e 
May be done.  Blood viscosity and platelet aggregation in 
volanesorsen-treatment naïve patients only 
 
Added:  archive blood sample for potential gene sequencing related to 
hypertriglyceridemia (Group 2 if not available from index study) 
Added troponin, 
platelet bound 
autoantibodies, 
and modified CBC 
blood draws to 
provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations. 
 
Added patient 
chart review, 
blood viscosity 
and potential 
gene sequencing 
to assess 
potential benefit of 
ISIS 304801 
administration. 
 
Added platelet 
aggregation to 
assess platelet 
function following 
ISIS 304801 
administration. 
Appendix A 
Added: 
Appendix A Schedule of Procedures – Extended Treatment Period Table 
and Legend. 
To allow patients 
who complete the 
52-week 
treatment period 
to participate in an 
expanded access 
program or 
continue dosing 
for up to an 
additional 
52 weeks until an 
expanded access 
program is 
approved and 
available in their 
country. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
 
11 April 2017 
 
27 
Protocol 
Section 
Description of Change 
Rationale 
Appendix B 
Removed Screening Tests (Group 3) 
 
Added: 
Troponin I2 
CK-MB2 
Platelet Bound Autoantibodies3 
Blood Viscosity3 
Platelet Aggregation3 
 
2 
All abnormal troponin samples will be rerun at the central laboratory and 
also analyzed for CK-MB 
3 
May be done 
Added troponin, 
CK-MB, and 
platelet bound 
autoantibodies, 
provide added 
patient safety. 
Added Blood 
Viscosity to 
assess potential 
benefit of 
ISIS 304801 
administration 
Added Platelet 
Aggregation to 
assess platelet 
function following 
ISIS 304801 
administration. 
Appendix C 
Added: 
Appendix C PK Sampling Schedule (Extended Treatment Period) Table. 
To collect 
intermittent PK 
data in patients 
who enter the 
extended 
treatment period. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
28 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will have the option of 
participating in an expanded access program or continuing dosing for up to 
an additional 52 weeks until an expanded access program is approved and 
available in their country.  Patients not participating in an expanded access 
program will enter a 13-week post-treatment evaluation period 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet 
the following criteria in order to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) supported by documentation of at least 1 of 
the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤20% of normal in medical 
history. Note: testing of LPL activity should not be performed to 
confirm eligibility for the study 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Qualification for 
the ISIS 304801-CS16 index study  
4. 
Able and willing to participate in a 65-week study 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
29 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2  
(ISIS 304801-CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the 
opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
30 
PROTOCOL SYNOPSIS Continued 
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
Option to participate in an extended treatment period (up to an 
additional 52 weeks) 
o 
A 13-week post-treatment evaluation period or expanded 
access program 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, blood 
viscosity, volanesorsen plasma concentrations, immunogenicity (IM) testing, 
platelet aggregation, liver/spleen magnetic resonance imaging (MRI), ECGs, 
echocardiograms and quality of life assessments will be performed according 
to the schedule of procedures in Appendix A.  Dietary counseling will be 
repeated at intervals throughout the treatment and follow-up period and a 
daily food/drink diary will be completed for the week prior to each quarterly 
visit by each patient.  Following the Week 52 visit, patients will have the 
option of participating in an expanded access program or continuing dosing 
for up to an additional 52 weeks until an expanded access program is 
approved and available in their country.  Patients not participating in an 
expanded access program will enter the 13-week post-treatment evaluation 
period. 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
31 
PROTOCOL SYNOPSIS Continued 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
• 
Platelet aggregation (may be evaluated) 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Change in blood viscosity (may be evaluated) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
32 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION (ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety 
assessments.  PK and PD/efficacy 
assessments at specified time points 
POST-TREATMENT 
EVALUATION PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD 
assessments 
Patients will have 
the option of 
participating in an 
expanded access 
program or 
continuing dosing 
for up to an 
additional 52 weeks 
until an expanded 
access program is 
approved and 
available in their 
country. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
33 
STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
glycosylphosphatidylinositol-anchored hdl-binding protein 1 
HAPI 
heritability and phenotype intervention 
HbA1c 
glycated hemoglobin 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein-cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
34 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein-cholesterol 
LMF1 
lipase maturation factor 1 
LPL 
lipoprotein lipase 
MACE 
major acute cardiovascular event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
no-observed-adverse-effect level 
non-HDL-C 
non-high-density lipoprotein-cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
triglyceride-rich lipoproteins 
ULN 
upper limit of normal 
VLDL 
very-low-density lipoprotein 
VLDL-C 
very-low-density lipoprotein-cholesterol 
VLDL-TG 
lipoprotein-triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive) 
A  G  C T T
C  T T G T C C A G C 
T T T A T 
Phosphorothioate 
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies, there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients will have the option of participating in an expanded access 
program or continuing dosing for up to an additional 52 weeks until an expanded access program 
is approved and available in their country.  Patients not participating in an expanded access 
program will enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Qualification 
A Qualification period of up to 2 weeks (unless approved by the Sponsor) is given to complete 
qualification assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and 
Appendix A. 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 7 Study Center visits on 
Weeks 53, 54, 55, 56, 57, 58, and 65 (Weeks 53, 54, 55, 56, 57, and 58 may be conducted by a 
home healthcare nurse). 
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 


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3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open-label study are performed.   
During the qualification period, the eligibility of the patient to enroll in the open-label study will 
be determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may 
be used for qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient 
identification number will be used to identify the patient throughout the extension trial and must 
be used on all study documentation related to that patient.  The patient identification number 
must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all qualification assessments 
have been completed and after the Investigator has verified that they are eligible per criteria in 
Sections 5.1 and 5.2.  No patient may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 


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3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
Group 2:  Patients who enrolled in ISIS 304801-CS16 must also meet the following 
criteria in order to enter into the open-label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
supported by documentation of at least 1 of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤20% of normal in medical history.  Note: 
testing of LPL activity should not be performed to confirm eligibility for the study 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Qualification for the ISIS 304801-CS16 
index study 
4. Able and willing to participate in a 65-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
*Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 
(ISIS 304801-CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 


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2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification  
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, blood viscosity, volanesorsen plasma 
concentrations, immunogenicity (IM) testing, platelet aggregation, liver/spleen MRI, ECGs, 
echocardiograms and quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Adverse events at the injection site should be collected as adverse 
events.  Dietary counseling will be reinforced at intervals throughout the treatment and follow-up 
period and all patients will complete a daily food diary for one week prior to their quarterly visit.  
All blood and urine samples should be collected prior to volanesorsen administration.  Blood 
sampling at Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51 
may be conducted by a home healthcare nurse.  Approval for study procedures to be conducted 
by a home healthcare nurse on other outpatient visit days will require prior approval by the 
Sponsor.  Patients must be fasted prior to drawing all blood samples and samples drawn locally 
should also be sent to the central laboratory for analysis whenever possible.  Dosing instructions 
and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.3 
Extended Treatment Period 
Patients will have the option of continuing dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country. 


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During the extended treatment period, patients will report to the study center for clinic visits 
during Weeks 54-104 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, volanesorsen plasma concentrations, IM testing, 
ECGs, and physical examinations will be performed according to the Schedule of Procedures in 
Appendix A.  Adverse events at the injection site should be collected as adverse events.  Dietary 
counseling will be reinforced at intervals throughout the extended treatment period.  All blood 
and urine samples should be collected prior to volanesorsen administration.  Blood sampling at 
Weeks 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 78, 
79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 
103 may be conducted by a home healthcare nurse.  Approval for study procedures to be 
conducted by a home healthcare nurse on other outpatient visit days will require prior approval 
by the Sponsor.  Patients must be fasted prior to drawing all blood samples and samples drawn 
locally should also be sent to the central laboratory for analysis whenever possible.  Dosing 
instructions and training will be provided to the patient where applicable. 
6.1.4 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.5 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of participating 
in an expanded access program or continuing dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country as described in 
Section 6.1.3.  Patients not participating in an expanded access program will enter the 13-week 
post-treatment evaluation period.  This 13-week post-treatment evaluation period consists of 
7 Study Center visits on Weeks 53, 54, 55, 56, 57, and 58 (which may be conducted by a home 
healthcare nurse), and Week 65 as outlined in the Schedule of Procedures in Appendix A.  
Patients who complete, or terminate early from, the extended treatment period without 
subsequently participating in an expanded access program will enter a 13-week post-treatment 
evaluation period consisting of 7 Study Center visits on Weeks 105, 106, 107, 108, 109, and 
110 (which may be conducted by a home healthcare nurse), and Week 117 as outlined in the 
Schedule of Procedures in Appendix A. 


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6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and the result must be reviewed by the Investigator and 
confirmed to be acceptable before dosing can continue.  All platelet count results will be 
promptly reviewed by the Investigator to determine if the count has met a stopping rule, or the 
dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 roll-over patients) and repeated at Week 52. 
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 


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6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65.  Patients in the Extended Treatment Period will have ECGs performed in triplicate at 
Week 76 and Week 104. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period (Week 65). 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service.  
Patients in the Extended Treatment Period will receive diet/alcohol counseling by 
qualified study personnel at clinic visits only. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet may be conducted randomly during the treatment and 
post treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 2) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior 
to Qualification and information relating to these events will be collected for independent 
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6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent† or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
* Note: A female condom and a male condom should not be used together as friction between 
the two can result in either product failing. 


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† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2 to 8 °C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 


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8.
TREATMENT OF PATIENTS
8.1 
Volanesorsen Administration
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example, if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 


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if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 


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4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3.  
Monitor every 1 week unless otherwise specified. 
Study Drug administration is contingent on the availability of the immediately preceding test 
result.  An interpretable platelet value must be available within 7 days prior to dosing.  Only the 
study doctor or qualified designee can authorize continued Study Drug administration based on 
an acceptable platelet value.  Patients should not administer a dose until they have been 
contacted by their study doctor or designee and told that it is acceptable to dose.  Authorization 
to dose must be documented in the patient’s medical records. 
Due to the 1 to 2-year study duration it is anticipated that patients may undertake travel including 
vacations, which may impede weekly platelet monitoring.  In some situations, it may be possible 
to arrange for local laboratory testing or use of the home healthcare service at their temporary 
location.  The intent is to maintain weekly platelet monitoring and dosing where possible, as well 
as Investigator site contact with the study patients.  However, if the above options are not 
possible, a temporary interruption of study treatment will be planned with a prompt blood draw 
upon the patient’s return which must be reported and reviewed by the Investigator prior to the 
patient resuming dosing. 
The tests outlined in Table 2 should also be performed as soon as possible.  Additional lab tests 
will be determined by the Sponsor Medical Monitor or designee in consultation with the 
Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
 
 


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Table 2 
Labs to Be Performed in the Event of a Platelet Count Less than the Lower 
Limit of Normal (x2) or < 100,000/mm3 (x1)* 
*In patients who have any 2 occurrences (consecutive or non-consecutive) of platelet count less 
than the lower limit of normal or who have any 1 occurrence of platelets < 100,000/mm3.  Labs 
only need to be performed once.  Labs may be collected over multiple visits, if blood 
requirements are a concern, as per investigator discretion. 
Note: 
The following labs may change as additional data is assessed, and sites will be updated 
regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicobacter pylori (breath test) 
Serology for: 
HBV, HCV, HIV (if not done recently for Qualification) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 
 


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8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 


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o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1-week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 


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The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event 
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 


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8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 
that occurs while the patient is on dosing at 300 mg every 2 weeks then dosing of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored as outlined in 
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Administration of steroids is recommended for patients whose platelet count is less than 
50,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note:  may require continuation with oral steroids after methylprednisolone).  Triglyceride 
levels be monitored weekly, and AE monitoring will continue, during corticosteroid treatment 
and the laboratory alert will be changed from an increase of 2,000 to 500 mg/dL during that 
period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks (refer to Section 8.7).  The suitability of the patient for continued dosing will be 
determined by the Investigator in consultation with the Study Medical Monitor and will be based 
on factors such as the original rate of decline in the patient’s platelet count, whether any bleeding 
events were experienced by the patient, and the speed of recovery of platelet count upon holding 
of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
 


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Table 3 
Actions in Patients with Low Platelet Count or Drop in Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
 
Study Drug administration is 
contingent on the availability of the 
immediately preceding test result.  An 
interpretable platelet value must be 
available within 7 days prior to dosing.  
Only the study doctor or qualified 
designee can authorize continued 
Study Drug administration based on an 
acceptable platelet value.  Patients 
should not administer a dose until they 
have been contacted by their study 
doctor or designee and told that it is 
acceptable to dose.  Authorization to 
dose must be documented in the 
patient’s medical records. 
Monitor every 1 week unless otherwise 
specified 
 
Obtain additional lab tests (Table 2) if 
2 occurrences consecutive or 
non-consecutive) of platelet count 140K - 
> 100K/mm3 or 1 occurrence of platelet 
count ≤ 100K/mm3.  Labs only need to be 
performed once.  Labs may be collected 
over multiple visits, if blood requirements 
are a concern, as per investigator 
discretion. 
> 100K/mm3 
Weekly 300 mg Study Drug 
administration 
100K/mm3 - > 75K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks 
 
75K/mm3 - > 50K/mm3 
• If occurs while on dose of 300 mg 
every 2 weeks then permanently 
discontinue Study Drug, otherwise 
dose pause 
• When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks 
only if approved by Sponsor 
Medical Monitor 
• Monitor every 2-3 days until 
2 successive values are > 75K/mm3 
then monitor every 1 week 
• Consider discontinuation of antiplatelet 
agents/NSAIDS/ anticoagulant 
medication 
≤ 50K/mm3 
Permanently discontinue Study Drug 
• Monitor daily until 2 successive values 
show improvement then monitor every 
2-3 days until 2 successive values are 
>75K/mm3 then monitor every 1 week 
• Patient should be evaluated by a 
hematologist to provide diagnostic and 
therapeutic management 
• Steroids recommended*.  It is strongly 
recommended that, unless the patient 
has a medical contraindication to 
receiving glucocorticoids, the patient 
receives glucocorticoid therapy to 
reverse the platelet decline 
• Monitor triglyceride levels weekly and 
continue AE monitoring during steroid 
therapy 
• Discontinue antiplatelet agents/ 
NSAIDS/ anticoagulant medication while 
platelet count is< 50K/mm3 if possible 
* 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or methylprednisolone 
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8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 3 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 
schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in in Section 8.6.3 for the first 6 weeks after discontinuing Study 
Drug.  Following this period, if the platelet count is stable (at least 3 consecutive values that are 
stable as determined by the Sponsor Medical Monitor and > 100,000/mm3), the next platelet 
count should be taken within at least 6 weeks so that patients are monitored for at least 12 weeks 
after discontinuing Study Drug.  Patients should also be strongly encouraged to attend applicable 
landmark visits at Weeks 12, 13, 25, 26, and 50, 52 (calculated based on the time elapsed since 
Day 1) to collect fasting lipid panels and conduct safety assessments in accordance with the 
Schedule of Procedures in Appendix A.  Any patient who discontinues treatment after Week 44 
should also be strongly encouraged to attend a final follow-up visit (Week 65 visit assessments) 
approximately 13 weeks after their last dose of Study Drug, in addition to the applicable 
landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 


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8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 3 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 
6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  
Patients should also be encouraged to undergo a final follow-up visit (Week 65 (or Week 117 if 
terminating from the Extended Treatment Follow-Up Period), see Appendix A) prior to leaving 
the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 


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8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 (or Week 117 if patient enters the extended treatment 
period) visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 


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9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 


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9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 


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9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit (or Week 117 if patient enters the 
extended treatment period).  When the Investigator is reporting by telephone, it is important to 
speak to someone in person versus leaving a message.  An Initial Serious Adverse Event Form 
should be completed and a copy should be faxed to the Sponsor or designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit 
(or Week 117 if patient enters the extended treatment period).  The Investigator will monitor 
each patient closely and record all observed or volunteered AEs on the Adverse Event Case 
Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
 
 


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• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 


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• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 


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9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 


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physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Change in blood viscosity (may be evaluated) 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 


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• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
• Platelet aggregation (may be evaluated) 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active 
Study Drug and have a baseline TG assessment.  The FAS represents the practically-feasible 
intent-to-treat (ITT) population as delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification).   
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline will be the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 


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10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group of the index studies for 
patients on active in the ISIS 304801-CS6 or ISIS 304801-CS16 index studies, and pooled 
treatment naive group which including patients on placebo in index studies.  Where appropriate, 
p-values will be reported.  All statistical tests will be conducted using 2-sided tests with 5% 
Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will 
be assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK 
endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group and overall.  The patient disposition will be summarized by treatment group and 
overall.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
and overall. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term 
and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 


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10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group.  Response rate of patients with fasting plasma TG 
< 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and 
Month 12 will be summarized.  Response analysis will also be conducted using a range of fasting 
plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group for other fasting lipid measures including non-HDL-C, apoB, 
HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 
2 patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the 
index study will receive the first treatment of volanesorsen (single-dose PK), while patients who 
received volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these 
patients reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time 
taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under 
the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration 
(CL0-24h /F) will be calculated from CL0-24h/F = Actual Dose/AUC0-24h.  Mean residence time 
(MRT) from time zero to 24 hours after the SC administration will be calculated from the 
equation, MRT0-24h = AUMC0-24h/AUC0-24h, where AUMC0-24h is the area under the moment 
plasma concentration-time curve from time zero to 24 hours after the SC administration.  Other 
PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 


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Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the last ADA sample 
collection day, and subject - peak titer if applicable, will be listed by their prior treatment in 
Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by treatment group.  Furthermore, onset and titer of the ADA 
response, if applicable, will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 


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informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 


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No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 


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13. 
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with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
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14. 
APPENDICES 
 
 
 


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Appendix A 
Schedule of Procedures 
 
 


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Appendix A Schedule of Procedures 
Study Period 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to  
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 44
9 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Echocardiography 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Blood Draw (Fasting)d 
Chemistry Panel 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC with Differentialc 
X 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
X 
Serum Lipid Panel 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Blood viscositye 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Platelet aggregatione 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Coagulation (aPTT, PT, INR) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Troponin I 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Platelet Bound Autoantibodiese 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK - Volanesorsen 
 
Xn 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Serum Pregnancy Testf 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
 
11 April 2017 
 
83 
Appendix A Schedule of Procedures Continued 
Study Period 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to 
 -1 
Wk 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
 
 
 
Wk 
25 
Wk 
26 
 
 
 
 
 
 
 
Wk 
50 
Wk 52 
or ET 
 
 
 
Study Day 
-14 to 
-7 
1 
2 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Blood Draw 
(Fasting)d 
Archive blood sample for 
potential gene sequencing 
related to hypertriglyceridemia 
(Group 2 if not available from 
index study)i 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Serum & Plasma 
Samplesg 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Urinalysisd 
X 
Xo 
 
X 
 
X 
 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
Xo 
Fundus Photographyh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Genetic testing for FCS diagnosis (if 
not available in medical history)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Food/Drink Diary (quarterly)j 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Diet/Alcohol Counselingk 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Qualification procedures performed (Please refer to Sections 3.4.1, 4.1, and 6.1.1) 
b 
Patient charts will be reviewed in order to collect data for events of acute pancreatitis or suspected pancreatitis in the patient’s medical history.  Chart review may 
be conducted at any time during the study.  These events will be adjudicated in the same manner as for events of pancreatitis during the study 
c 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally.  In 
the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 
1 week and the result must be reviewed by the Investigator and confirmed to be acceptable before dosing can continue.  All platelet count results will be promptly 
reviewed by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 75,000/mm3.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
 
11 April 2017 
 
84 
Appendix A Schedule of Procedures Continued 
Legend Text Continued 
d 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
e 
May be done.  Blood viscosity and platelet aggregation in volanesorsen-treatment naïve patients only 
f 
Females of childbearing potential only 
g 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of 
volanesorsen 
h 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 [ISIS 304801-CS16 roll-over patients]) 
and repeated at Week 52 (Please refer to Section 6.2.2.2) 
i 
Genetic testing can be conducted for study qualification (Group 2 [ISIS 304801-CS16 roll-over patients]); genetic testing will only be conducted if allowed in 
the geographic region and only after the patient has given specific written informed consent for genetic testing 
j 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
k 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
l 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
m 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
n 
Full or abbreviated PK profile (see Appendix C) 
o 
Expanded urinalysis (see Appendix B) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
 
11 April 2017 
 
85 
Appendix A Schedule of Procedures – Extended Treatment Period 
Study Period 
Treatment Period 
Post-Treatment 
Follow-up 
Study Week 
Wk 54 
& 56 
Wk 
58 
Wk 60 
& 62 
Mo 15 
Wk 64 
Wk 66 
& 68 
Wk 
70 
Wk 72 
& 74 
Mo 18 
Wk 76 
Wk 78 
& 80 
Wk 
82 
Wk 84, 
86, & 88 
Mo 21 
Wk 90 
Wk 92 
& 94 
Wk 
96 
Wk 
98, 
100 & 
102 
Mo 24 
Wk 
104 
Wk 
106 
& 
108 
Wk 
110 
Mo 27 
Wk 
117 
Study Day 
372 & 
386 
400 414 & 
428  
442 
456 & 
470 
484 498 & 
512 
526 
540 & 
554 
56
8  
582, 596 
& 610 
624 
638 & 
652 
666 
680, 
694 & 
708 
722 
736  
& 
750 
764 
813 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Outpatient Visit 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
X 
Vital Signs (+ body weight) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis(including P/C ratio) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood Draw (Fasting)b 
Chemistry Panel 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CBC with Differentiala 
X 
Platelets are assessed each calendar week, visits do not have specified windows to allow flexibility of scheduling. 
X 
Serum Lipid Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Troponin I 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 304801c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-ISIS 304801 Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Serum Pregnancy Testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Weekly Study Drug: SC Injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diet/Alcohol Counselinge 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
 
11 April 2017 
 
86 
Appendix A Schedule of Procedures – Extended Treatment Period Continued 
Legend Text 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1 week and the result must be reviewed by the Investigator and confirmed to be acceptable before dosing can continue.  All platelet count results will be 
promptly reviewed by the Investigator to determine if the count has met a stopping rule, or the dose reduction rule of 100,000/mm3, or the dose pause rule of 
75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration 
c 
Abbreviated PK collection (see Appendix C) 
d 
Females of childbearing potential only 
e 
To reinforce compliance to the diet and alcohol restrictions 
f 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
87 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
88 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
Troponin I2 
• 
CK-MB2 
• 
Platelet Bound 
Autoantibodies3 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
• 
Blood viscosity3 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination4 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
Platelet Function 
• 
Platelet aggregation3 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
3 
May be done 
4 
Will be performed on abnormal findings unless otherwise specified 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
89 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
90 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (Extended Treatment Period) 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Study Day 
D526 
D722 
D813 
Visit Window 
+/- Days 
2 
2 
7 
Time Point 
Pre-dose  
Pre-dose 
Anytime 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
91 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
92 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
93 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - Netherlands 
11 April 2017 
 
94 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 6 – 18 November 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304801-CS7 
Protocol 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 6 
18 November 2016 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 6- 18 November 2016 
Protocol History: 
Original Protocol: 
Protocol Amendment 1 : 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Protocol Amendment 5: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
MD, MBA 
28 August 2015 
2 February 2016 
22 April2016 
9 May 2016 
6June2016 
6July2016 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 6 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
18 November 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 6 
Date: 
18 November 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 18 November 2016, and agree to conduct the study 
as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.................................................................................................... 10 
PROTOCOL SYNOPSIS ........................................................................................................... 15 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 21 
STUDY GLOSSARY .................................................................................................................. 22 
1. 
OBJECTIVES ................................................................................................................. 24 
2. 
BACKGROUND AND RATIONALE .......................................................................... 24 
2.1 
Overview of Disease ......................................................................................................24 
2.2 
Therapeutic Rationale ....................................................................................................25 
2.3 
Volanesorsen ..................................................................................................................26 
2.3.1 
Mechanism of Action .............................................................................................26 
2.3.2 
Chemistry ...............................................................................................................27 
2.3.3 
Preclinical Experience ............................................................................................28 
2.3.4 
Clinical Experience ................................................................................................29 
2.4 
Rationale for Dose and Schedule of Administration .....................................................30 
3. 
EXPERIMENTAL PLAN .............................................................................................. 31 
3.1 
Study Design ..................................................................................................................31 
3.2 
Number of Study Centers ..............................................................................................31 
3.3 
Number of Patients ........................................................................................................31 
3.4 
Overall Study Duration and Follow-up .........................................................................31 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification ....................................................................................31 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/ 
Qualification ...........................................................................................................31 
3.4.3 
Treatment ................................................................................................................31 
3.4.4 
Post-Treatment .......................................................................................................32 
3.5 
End-of-Study ..................................................................................................................32 
3.6 
Data and Safety Monitoring Board ................................................................................32 
4. 
PATIENT ENROLLMENT ........................................................................................... 32 
4.1 
Screening/Qualification .................................................................................................32 
4.2 
Enrollment .....................................................................................................................33 
5. 
PATIENT ELIGIBILITY .............................................................................................. 33 
5.1 
Inclusion Criteria ...........................................................................................................33 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-CS16) 
Index Study Roll-over Patients ......................................................................................34 
6. 
STUDY PROCEDURES ................................................................................................ 36 
6.1 
Study Schedule ..............................................................................................................36 
6.1.1 
Qualification (Groups 1 and 2) ...............................................................................37 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
6 
6.1.2 
Screening and Qualification (Group 3) ..................................................................37 
6.1.3 
Treatment Period ....................................................................................................37 
6.1.4 
Extended Treatment Period ....................................................................................38 
6.1.5 
Pharmacokinetic (PK) Subgroup ............................................................................38 
6.1.6 
Post-Treatment Period ............................................................................................38 
6.2 
Additional Study Assessments .......................................................................................39 
6.2.1 
Laboratory Assessments .........................................................................................39 
6.2.2 
Physical Exams and Vital Signs .............................................................................39 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................39 
6.2.2.2 
Lipemia Retinalis .............................................................................................39 
6.2.3 
Echocardiography ...................................................................................................40 
6.2.4 
ECG ........................................................................................................................40 
6.2.5 
MRI ........................................................................................................................40 
6.2.6 
Quality of Life Assessments ...................................................................................40 
6.2.7 
Disease Symptom Diary .........................................................................................40 
6.2.8 
Diet Monitoring ......................................................................................................40 
6.2.9 
Family History ........................................................................................................40 
6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 3) ..41 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................41 
6.3.1 
Contraception Requirements ..................................................................................41 
6.3.2 
Other Requirements ................................................................................................42 
7. 
STUDY DRUG ................................................................................................................ 42 
7.1 
Volanesorsen Description ..............................................................................................42 
7.2 
Packaging and Labeling .................................................................................................42 
7.3 
Study Drug Accountability ............................................................................................43 
8. 
TREATMENT OF PATIENTS ..................................................................................... 43 
8.1 
Volanesorsen Administration ........................................................................................43 
8.2 
Other Protocol-Required Drugs .....................................................................................43 
8.3 
Other Protocol-Required Treatment Procedures ............................................................43 
8.4 
Treatment Precautions ...................................................................................................43 
8.5 
Safety Monitoring Rules ................................................................................................43 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................44 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................45 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................46 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................47 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................47 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........47 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................47 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................48 
8.5.9 
Acute Pancreatitis ...................................................................................................49 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
7 
8.6 
Stopping Rules ...............................................................................................................49 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................49 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................50 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................50 
8.7 
Adjustment of Dose Frequency .....................................................................................52 
8.8 
Discontinuation of Study Treatment ..............................................................................53 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................53 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .53 
8.9 
Withdrawal of Patients from the Study ..........................................................................54 
8.10 
Concomitant Therapy and Procedures ...........................................................................54 
8.10.1 
Concomitant Therapy .............................................................................................54 
8.10.2 
Concomitant Procedures .........................................................................................55 
8.11 
Treatment Compliance ...................................................................................................55 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 55 
9.1 
Sponsor Review of Safety Information .........................................................................55 
9.2 
Regulatory Requirements ..............................................................................................55 
9.3 
Definitions .....................................................................................................................56 
9.3.1 
Adverse Event ........................................................................................................56 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................56 
9.3.3 
Serious Adverse Event (SAE) ................................................................................57 
9.4 
Monitoring and Recording Adverse Events ...................................................................57 
9.4.1 
Serious Adverse Events ..........................................................................................57 
9.4.2 
Non-Serious Adverse Events ..................................................................................58 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................58 
9.4.3.1 
Relationship to the Study Drug ........................................................................58 
9.4.3.2 
Severity ............................................................................................................58 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................59 
9.4.3.4 
Treatment Given for Adverse Event ................................................................59 
9.4.3.5 
Outcome of the Adverse Event ........................................................................59 
9.4.4 
Adjudication Committees .......................................................................................60 
9.5 
Procedures for Handling Special Situations ..................................................................60 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................60 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............60 
9.5.3 
Dosing Errors .........................................................................................................61 
9.5.4 
Contraception and Pregnancy .................................................................................61 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 62 
10.1 
Study Endpoints .............................................................................................................62 
10.1.1 
Efficacy Endpoints .................................................................................................62 
10.1.2 
Safety Endpoints .....................................................................................................62 
10.2 
Sample Size ....................................................................................................................62 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
8 
10.3 
Populations .....................................................................................................................63 
10.4 
Definition of Baseline ....................................................................................................63 
10.5 
Interim Analysis .............................................................................................................63 
10.6 
Planned Methods of Analysis ........................................................................................63 
10.6.1 
Demographic and Baseline Characteristics ............................................................64 
10.6.2 
Safety Analysis .......................................................................................................64 
10.6.3 
Efficacy Analysis ...................................................................................................64 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................65 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................65 
10.6.4.2 
Immunogenicity Analysis ................................................................................65 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 66 
11.1 
Informed Consent ..........................................................................................................66 
11.2 
Ethical Conduct of the Study .........................................................................................66 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................67 
11.4 
Patient Confidentiality ...................................................................................................67 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 67 
12.1 
Protocol Amendments ....................................................................................................67 
12.2 
Study Termination .........................................................................................................68 
12.3 
Study Documentation and Storage ................................................................................68 
12.4 
Study Monitoring ...........................................................................................................69 
12.5 
Language ........................................................................................................................69 
12.6 
Compensation for Injury ................................................................................................69 
13. 
REFERENCES ................................................................................................................ 70 
14. 
APPENDICES ................................................................................................................. 72 
Appendix A 
Schedule of Procedures ....................................................................................73 
Appendix B 
List of Laboratory Analytes .............................................................................79 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................81 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......83 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics .........................................................42 
Table 2 
Labs to Be Performed in the Event of a Platelet Count < 75,000/mm3 .................46 
Table 3 
Actions in Patients with Low Platelet Count .........................................................52 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence ...................................................................................56 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
9 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms ...............25 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ....................................27 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen ...............29 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
10 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
6 
Amendment Date: 
18 November 2016 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 5 dated 6 July 2016: 
1. To allow patients who complete the 52-week treatment period to participate in an 
expanded access program or continue dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country.  Patients not 
participating in an expanded access program will enter the 13-week post treatment 
evaluation period. 
2. The following assessments were added:  Troponin I; labs to be performed in the event of 
a platelet count < 75,000/mm3; platelet bound autoantibody testing at baseline (may be 
done); plus medical history, hepatitis B, C, and HIV at Screening (Group 3 patients). 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 
The following table provides a summary list of major changes to the protocol: 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:   
Study Design  
Study Visit Schedule 
and Procedures 
3.1  Study Design 
6.1.6  Post-Treatment 
Period 
Was: 
Following the Week 52 visit, patients will enter a 13-week 
post treatment evaluation period. 
Is: 
Following the Week 52 visit, patients will have the option of 
participating in an expanded access program or continuing 
dosing for up to an additional 52 weeks until an expanded 
access program is approved and available in their country.  
Patients not participating in an expanded access program 
will enter a 13-week post-treatment evaluation period. 
To allow patients the 
option of continuing 
treatment with 
volanesorsen after 
completion of the 
52-week open-label 
treatment period. 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
11 
Protocol Section 
Description of Change 
Rationale 
For consistency with the above changes: 
appropriate wording was added to the following sections: 
Protocol Synopsis:  Study Visit Schedule and Procedures 
Study Design and Treatment Schema 
6.2.4  ECG 
6.2.7  Disease Symptom Diary 
6.2.8  Diet Monitoring 
8.8.2  Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
8.10.2  Concomitant Procedures 
9.4.2  Non-Serious Adverse Events 
and the following table and footnotes were added to Appendix A:  Schedule of Procedures: 
Appendix A 
Schedule of Procedures – Extended Treatment Period 
Study Period 
Treatment Period 
Post-Treatment 
Follow-up 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
60 
& 
62 
Mo 
15 
Wk 
64 
Wk 
66 
& 
68 
Wk 
70 
Wk 
72 
& 
74 
Mo 
18 
Wk  
76 
Wk 
78 
& 
80 
Wk 
82 
Wk 
84, 
86 
& 
88 
Mo 
21 
Wk 
90 
Wk 
92 
& 
94 
Wk 
96  
Wk 
98, 
100 
& 
102 
Mo 
24 
Wk 
104 
Wk 
106 
& 
108 
Wk 
110 
Mo 
27 
Wk 
117 
Study Day 
372 
& 
386 
400 
414 
& 
428 
442 
456 
& 
470 
484 
498 
& 
512 
526 
540 
& 
554 
568 
582, 
596 
& 
610 
624 
638 
& 
652 
666 
680, 
694 
& 
708 
722 
736  
& 
750 
764 
813 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Outpatient Visit 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
X 
Vital Signs (+ body 
weight) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis (including 
P/C ratio) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood Draw (Fasting)b 
Chemistry Panel 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CBC with 
Differentiala 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid 
Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Coagulation 
(aPTT, PT, INR) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Troponin I 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Plasma PK -  
ISIS 304801c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-ISIS 304801 
Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Serum 
Pregnancy Testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Weekly Study Drug: SC 
Injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diet/Alcohol 
Counselinge 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication  X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
12 
Protocol Section 
Description of Change 
Rationale 
Appendix A 
Schedule of Procedures – Extended Treatment Period Continued 
Legend Text 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample 
should be collected in parallel and analyzed locally.  In the event that both the central and local sample are 
unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 
1 week and determined not to have met a stopping rule before dosing can continue.  If there is no reportable 
platelet count within 14 days of the last platelet count, the Investigator will contact the patient to hold dosing 
until a new platelet count is obtained and reviewed.  All platelet count results will be promptly reviewed by the 
Investigator to ensure that the count has not met the stopping rule and to determine whether the rate of 
decline is suggestive that the patient could be approaching the dose pause rule of 75,000/mm3.  Any case of a 
platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 
12 hours.  During treatment period urine and blood samples will be collected prior to Study Drug 
administration 
c 
Abbreviated PK collection (see Appendix C) 
d 
Females of childbearing potential only 
e 
To reinforce compliance to the diet and alcohol restrictions 
f 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as 
arranged by the Study Center personnel 
 
and the following table and footnotes were added to Appendix C:  Pharmacokinetic Sampling Schedule: 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
PK Sampling Schedule:  Extended Treatment Schedule 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Study Day 
D526 
D722 
D813 
Visit Window 
+/- Days 
2 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Anytime 
 
 
6.1.4  Extended 
Treatment Period 
Added 
Patients will have the option of continuing dosing for up to 
an additional 52 weeks until an expanded access program is 
approved and available in their country. 
During the extended treatment period, patients will report to 
the study center for clinic visits during Weeks 54-104 (see 
Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly unless the patient is on a 
biweekly dosing schedule for safety reasons (Section 8.1).  
Collection and measurement of vital signs, clinical laboratory 
parameters (including hematology, serum chemistry, and 
urinalysis), AEs, concomitant medication/procedure 
information, lipid panel, volanesorsen plasma 
concentrations, IM testing, ECGs, and physical 
examinations will be performed according to the schedule of 
procedures in Appendix A. 
To outline the 
procedures to be 
performed during the 
extended treatment 
period. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
13 
Protocol Section 
Description of Change 
Rationale 
6.1.4  Extended 
Treatment Period 
Continued 
Adverse events at the injection site should be collected as 
adverse events.  Dietary counseling will be reinforced at 
intervals throughout the extended treatment period.  All 
blood and urine samples should be collected prior to 
volanesorsen administration.  Blood sampling at Weeks 54, 
56, 58, 60, 62, 66, 68, 70, 72, 74, 78, 80, 82, 84, 86, 88, 92, 
94, 96, 98, 100, and 102 may be conducted by a home 
healthcare nurse.  Approval for study procedures to be 
conducted by a home healthcare nurse on other outpatient 
visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples 
and samples drawn locally should also be sent to the central 
laboratory for analysis whenever possible.  Every effort 
should be made to ensure the previous week’s dose is given 
7 days prior to a scheduled clinic visit.  Dosing instructions 
and training will be provided to the patient where applicable. 
To outline the 
procedures to be 
performed during the 
extended treatment 
period. 
6.1.6  Post-Treatment 
Period 
Added: 
Patients who complete, or terminate early from, the 
extended treatment period without subsequently 
participating in an expanded access program will enter a 
13-week post-treatment evaluation period consisting of 
4 Study Center visits on Weeks 106, 108, and 110 (which 
may be conducted by a home healthcare nurse), and 
Week 117 as outlined in the Schedule of Procedures in 
Appendix A. 
To describe the follow-up 
visits for patients that 
terminate early from the 
extended treatment 
period. 
6.2.10  Chart Review 
for Incidents of Acute 
Pancreatitis in Medical 
History (Group 3) 
Appendix A:  Schedule 
of Procedures 
Added: 
Patient records will be reviewed for incidents of acute 
pancreatitis occurring up to 5 years prior to screening and 
information relating to these events will be collected for 
independent adjudication. 
To collect acute 
pancreatitis medical 
history events on 
patients that did not 
participate in an index 
study (ISIS 304801-CS6 
or ISIS 304801-CS16). 
8.5.2  Safety 
Monitoring for Platelet 
Count Results 
Added: 
Table 2  Labs to Be Performed in the Event of a Platelet 
Count < 75,000/mm3. 
Note:  The following labs may change as additional data is 
assessed, and sites will be updated regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and 
sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
 
 
To increase platelet 
count monitoring for 
safety purposes. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
14 
Protocol Section 
Description of Change 
Rationale 
8.5.2  Safety 
Monitoring for Platelet 
Count Results 
Continued 
To Be Performed at Central Lab Continued 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
To increase platelet 
count monitoring for 
safety purposes. 
Section 10.3  
Populations 
Updated: 
Full Analysis Set (FAS):  All patients who are enrolled and 
received at least 1 dose of active Study Drug and have a 
baseline TG assessment. 
PK Population:  All patients who are enrolled, receive at 
least 1 dose of volanesorsen, and have at least 1 post first 
dose PK sample collected, analyzed, and reported.   
Modified to include, in 
the FAS, only those 
patients that are 
randomized and dosed 
and have a baseline TG 
assessment and clarified 
the PK Population. 
Section 10.4  
Definition of Baseline 
Added:  
For Group 3 patients, the baseline for fasting lipid 
measurements is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 in this 
open-label study, and the baseline for other assessments is 
defined as the last non-missing assessment prior to the first 
dose of Study Drug. 
To add the baseline 
definition for Group 3 
patients. 
Appendix A:  Schedule 
of Procedures 
Appendix B:  List of 
Laboratory Analytes 
Added: 
Troponin I at Screening (Group 3 patients only) and 
Weeks 13, 26, 52, and 65 (All abnormal troponin samples 
will be rerun at the central laboratory and also analyzed for 
CK-MB). 
Platelet bound autoantibody testing at baseline (may be 
done). 
Medical history, hepatitis B, C, and HIV at Screening 
(Group 3 patients only). 
To ensure that Troponin I 
is monitored in patients 
that did not previously 
receive volanesorsen 
(i.e., Group 3 patients 
and placebo patients 
from the index studies) 
consistently with what 
was done in the 
ISIS 304801-CS6 index 
study. 
To increase platelet 
count monitoring for 
safety purposes. 
To make the eligibility 
criteria for the Group 3 
patients consistent with 
those for the 
ISIS 304801-CS6 index 
study patients. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
15 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will have the option of 
participating in an expanded access program or continuing dosing for up to 
an additional 52 weeks until an expanded access program is approved and 
available in their country.  Patients not participating in an expanded access 
program will enter a 13-week post-treatment evaluation period 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order 
to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for 
the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label 
study  
4. 
Able and willing to participate in a 65-week study 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
16 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-
CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the 
opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage 
or addition of new medication within 12 weeks of screening [with the 
exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to screening 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) Continued 
4. History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of screening 
5. Any of the following laboratory values at Screening 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Screening 
d. 
LDL-C > 130 mg/dL at Screening 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully 
treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1 month of screening, or 5 half-lives of investigational agent, 
whichever is longer 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) Continued 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to screening and dose and 
regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
screening unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to screening and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to screening and dose and regimen expected to remain 
constant during the treatment period 
f. Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening and dose and regimen expected to 
remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to screening or planned during 
the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening 
(Occasional or intermittent use of over-the-counter medications will be 
allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of 
> 499 mL within 60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or the 
Sponsor would make the patient unsuitable for inclusion, or could 
interfere with the patient participating in or completing the study 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
 
 


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PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up to 
2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A 
• 
Group 3 patients (did not participate in an index study):  An up to 
8-week screening and qualification period, including a diet 
stabilization period of at least 6 weeks (screening and diet 
stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease 
management prior to screening).  Please refer to Section 6.1.2 and 
Appendix A 
• 
All patients: 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
Option to participate in an extended treatment period (up to an 
additional 52 weeks) 
o 
A 13-week post-treatment evaluation period or expanded 
access program 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will have the option of participating in an 
expanded access program or continuing dosing for up to an additional 
52 weeks until an expanded access program is approved and available in 
their country.  Patients not participating in an expanded access program will 
enter the 13-week post-treatment evaluation period. 
 
 


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PROTOCOL SYNOPSIS Continued 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
SCREENING PERIOD 
Weeks -8 to -2 (Group 3 patients only) 
QUALIFICATION PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION (ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety 
assessments.  PK and PD/efficacy 
assessments at specified time points 
POST-TREATMENT 
EVALUATION PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD 
assessments 
Patients will have 
the option of 
participating in an 
expanded access 
program or 
continuing dosing 
for up to an 
additional 52 weeks 
until an expanded 
access program is 
approved and 
available in their 
country. 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
glycosylphosphatidylinositol-anchored hdl-binding protein 1 
HAPI 
heritability and phenotype intervention 
HbA1c 
glycated hemoglobin 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein-cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein-cholesterol 
LMF1 
lipase maturation factor 1 
LPL 
lipoprotein lipase 
MACE 
major acute cardiovascular event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
no-observed-adverse-effect level 
non-HDL-C 
non-high-density lipoprotein-cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
triglyceride-rich lipoproteins 
ULN 
upper limit of normal 
VLDL 
very-low-density lipoprotein 
VLDL-C 
very-low-density lipoprotein-cholesterol 
VLDL-TG 
lipoprotein-triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll-over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll-over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or  
ISIS 304801-CS16 index studies 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients will have the option of participating in an expanded access 
program or continuing dosing for up to an additional 52 weeks until an expanded access program 
is approved and available in their country.  Patients not participating in an expanded access 
program will enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification 
A period of up to 2 weeks (unless approved by the Sponsor) is given to complete qualification 
assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and Appendix A. 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification 
An up to 8-week screening and qualification period, including a diet stabilization period of at 
least 6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if 
the patient is following a diet for optimal control of TGs and disease management prior to 
screening.  Please refer to Section 6.1.2 and Appendix A. 
3.4.3 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 


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3.4.4 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 4 Study Center visits on 
Weeks 54, 56, 58, and 65 (Weeks 54, 56, and 58 may be conducted by a home healthcare nurse). 
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Screening/Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open-label study are performed.   
Groups 1 and 2 (Qualification):  During the qualification period, the eligibility of the patient to 
enroll in the open-label study will be determined.  Final assessments from the ISIS 304801-CS6 
or ISIS 304801-CS16 studies may be used for qualification.  A period of up to 2 weeks after 
completion of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the 
Sponsor) is given to complete qualification.  Qualified patients will retain the unique patient 
identification number that was assigned to them during the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies.  The patient identification number will be used to identify the 
patient throughout the extension trial and must be used on all study documentation related to that 
patient.  The patient identification number must remain constant throughout the extension trial. 
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered 
enrolled into the study and will be assigned a unique screening number before any study 
procedures, including screening procedures, are performed.  At the time of enrollment, patients 
will be assigned a unique patient identification number.  This number will be used to identify the 
patient throughout the trial and must be used on all study documentation related to that patient.  
The screening number and patient identification number must remain constant throughout the 
entire trial.  In the event the patient is re-consented and re-screened the patient must be given a 
new screening number.  Screening numbers and patient identification numbers, once assigned, 
will not be re-used. 


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4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all Screening (Group3) and 
qualification assessments have been completed and after the Investigator has verified that they 
are eligible per criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to 
enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
Groups 2 and 3:  Patients must also meet the following criteria in order to enter into the 
open-label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
c. Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the  
 
ISIS 304801-CS16 index study 
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label study 
4. Able and willing to participate in a 65-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 


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involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-
CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 
Exclusion Criteria for Group 3 (patients who did not participate in an index study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of screening [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening 
4. History within 6 months of screening of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack 
or unstable congestive cardiac failure requiring a change in medication or major surgery 
within 3 months of screening 
5. Any of the following laboratory values at Screening 
a. Hepatic: 


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• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• ALT > 2.0 x ULN 
• AST > 2.0 x ULN 
b. Renal: 
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick.  In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs 
• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick.  In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field 
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Screening 
d. LDL-C > 130 mg/dL at Screening 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1-month 
of screening, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 


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14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable 
dose for at least 3 months prior to screening and dose and regimen expected to remain 
constant during the treatment period.  Patients taking OTC omega-3 fatty acids should 
make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening unless 
approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to screening and dose and regimen expected to remain 
stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
screening and dose and regimen expected to remain constant during the treatment 
period 
f. Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to screening and regular clinical monitoring is 
performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to screening and dose and regimen expected to remain constant during the treatment 
period 
i. Plasma apheresis within 4 weeks prior to screening or planned during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 
60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or 
placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the patient participating 
in or completing the study 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 


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6.1.1 
Qualification (Groups 1 and 2) 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  An 8-week period, including a diet stabilization period of at least 
6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease management prior to screening) 
is given to perform the screening evaluations.  The qualification assessments will be performed 
at Week -2 to -1, ideally after patient eligibility has been determined, and on Study Day 1.  
Abnormal screening results may be retested for review by the Study Medical Monitor for 
eligibility purposes 
6.1.3 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 2.5, 
4, 6, 8, 10, 12, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 40, 42, 44, 46, 48, and 50 may be 
conducted by a home healthcare nurse.  Approval for study procedures to be conducted by a 
home healthcare nurse on other outpatient visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples and samples drawn locally should also 
be sent to the central laboratory for analysis whenever possible.  Every effort should be made to 
ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  Dosing 
instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 


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6.1.4 
Extended Treatment Period 
Patients will have the option of continuing dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country. 
During the extended treatment period, patients will report to the study center for clinic visits 
during Weeks 54-104 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly unless the patient is on a biweekly dosing schedule for safety reasons 
(Section 8.1).  Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), AEs, concomitant 
medication/procedure information, lipid panel, volanesorsen plasma concentrations, IM testing, 
ECGs, and physical examinations will be performed according to the Schedule of Procedures in 
Appendix A.  Adverse events at the injection site should be collected as adverse events.  Dietary 
counseling will be reinforced at intervals throughout the extended treatment period.  All blood 
and urine samples should be collected prior to volanesorsen administration.  Blood sampling at 
Weeks 54, 56, 58, 60, 62, 66, 68, 70, 72, 74, 78, 80, 82, 84, 86, 88, 92, 94, 96, 98, 100, and 102 
may be conducted by a home healthcare nurse.  Approval for study procedures to be conducted 
by a home healthcare nurse on other outpatient visit days will require prior approval by the 
Sponsor.  Patients must be fasted prior to drawing all blood samples and samples drawn locally 
should also be sent to the central laboratory for analysis whenever possible.  Every effort should 
be made to ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  
Dosing instructions and training will be provided to the patient where applicable. 
6.1.5 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.6 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of participating 
in an expanded access program or continuing dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country as described in 
Section 6.1.4.  Patients not participating in an expanded access program will enter the 13-week 
post-treatment evaluation period.  This 13-week post-treatment evaluation period consists of 
4 Study Center visits on Weeks 54, 56, and 58 (which may be conducted by a home healthcare 
nurse), and Week 65 as outlined in the Schedule of Procedures in Appendix A.  Patients who 
complete, or terminate early from, the extended treatment period without subsequently 
participating in an expanded access program will enter a 13-week post-treatment evaluation 


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period consisting of 4 Study Center visits on Weeks 106, 108, and 110 (which may be conducted 
by a home healthcare nurse), and Week 117 as outlined in the Schedule of Procedures in 
Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and determined not to have met a stopping rule before dosing 
can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to ensure that the count 
has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 roll-over patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 


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6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65.  Patients in the Extended Treatment Period will have ECGs performed in triplicate at 
Week 76 and Week 104. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period (Week 65). 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service.  
Patients in the Extended Treatment Period will receive diet/alcohol counseling by 
qualified study personnel at clinic visits only. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet may be conducted randomly during the treatment and 
post treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 


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6.2.10 
Chart Review for Incidents of Acute Pancreatitis in Medical History (Group 3) 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior 
to screening and information relating to these events will be collected for independent 
adjudication. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent† or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 


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condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
* Note: A female condom and a male condom should not be used together as friction between 
the two can result in either product failing. 
† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2 to 8 °C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 


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7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 


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In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 


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Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3. 
The tests outlined in Table 2 should also be performed as soon as possible.  Additional lab tests 
will be determined by the Sponsor Medical Monitor or designee in consultation with the 
Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
 
 


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Table 2 
Labs to Be Performed in the Event of a Platelet Count < 75,000/mm3 
Note: The following labs may change as additional data is assessed, and sites will be updated 
regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 


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8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 


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≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1-week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 


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In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 


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1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3  below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 25,000/mm3, or a platelet count less than 75,000/mm3 
that occurs while the patient is on dosing at 300 mg every 2 weeks or 150 mg every week then 
dosing of a patient with volanesorsen will be stopped permanently.  Platelet count will be 
monitored daily until 2 successive values show improvement then monitored every 2-3 days until 
platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 


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0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone). 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks or a reduced dose of 150 mg per week (refer to Section 8.7).  The suitability of the 
patient for continued dosing will be determined by the Investigator in consultation with the Study 
Medical Monitor and will be based on factors such as the original rate of decline in the patient’s 
platelet count, whether any bleeding events were experienced by the patient, and the speed of 
recovery of platelet count upon holding of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Following a rechallenge platelet count should be tested every week until count is stable. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 


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Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every 1 week until stable* 
75K-100K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 1 week 
50K-75K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor  
Closer observation 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
< 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended** 
Consider need for hospitalization 
and referral to hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
At least 3 consecutive values measured weekly that are stable as determined by the Sponsor Medical Monitor 
and > 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methyl prednisolone) 
 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 3 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 


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schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in Table 3 in Section 8.6.3 for the first 6 weeks after 
discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3), the next platelet count should be taken within at least 6 weeks so that patients 
are monitored for at least 12 weeks after discontinuing Study Drug.  Patients should also be 
strongly encouraged to attend applicable landmark visits at Weeks 12, 13, 25, 26, and 50, 52 
(calculated based on the time elapsed since Day 1) to collect fasting lipid panels and conduct 
safety assessments in accordance with the Schedule of Procedures in Appendix A.  Any patient 
who discontinues treatment after Week 44 should also be strongly encouraged to attend a final 
follow-up visit (Week 65 visit assessments) approximately 13 weeks after their last dose of 
Study Drug, in addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 3 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 
6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  


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Patients should also be encouraged to undergo a final follow-up visit (Week 65 (or Week 117 if 
terminating from the Extended Treatment Follow-Up Period), see Appendix A) prior to leaving 
the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 


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Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 (or Week 117 if patient enters the extended treatment 
period) visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 


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Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 4 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 


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A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 


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follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit 
(or Week 117 if patient enters the extended treatment period).  The Investigator will monitor 
each patient closely and record all observed or volunteered AEs on the Adverse Event Case 
Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 


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• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 


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• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
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• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 


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10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and received at least 1 dose of active 
Study Drug and have a baseline TG assessment.  The FAS represents the practically-feasible 
intent-to-treat (ITT) population as delineated in ICH Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 post first dose PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification).  
For Group 3 patients, the baseline for fasting lipid measurements is defined as the average of 
Day 1 pre-dose assessment and the last measurement prior to Day 1 in this open-label study. 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study and 
Group 3 patients, baseline will be the last non-missing assessment prior to the first dose of 
Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group of the index studies for 
patients on active in the ISIS 304801-CS6 or ISIS 304801-CS16 index studies, and pooled 
treatment naive group which including patients on placebo in index studies and Group 3 patients.  


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Where appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided 
tests with 5% Type I error rates unless otherwise stated. 
TG related endpoints will be assessed in the FAS and PPS, and all other efficacy endpoints will 
be assessed in the FAS.  All safety assessments will be performed on the Safety Set.  PK 
endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group and overall.  The patient disposition will be summarized by treatment group and 
overall.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
and overall. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term 
and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group.  Response rate of patients with fasting plasma TG 
< 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, Month 6, and 
Month 12 will be summarized.  Response analysis will also be conducted using a range of fasting 
plasma TG thresholds for determination of responder status. 


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Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group for other fasting lipid measures including non-HDL-C, apoB, 
HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics by treatment group and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 2 
patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the index 
study (and all patients in Group 3) will receive the first treatment of volanesorsen (single-dose 
PK), while patients who received volanesorsen in the index studies had been on volanesorsen 
treatment for 12 months (ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data 
collected from these patients reflect steady-state PK.  The maximum observed drug 
concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  Area under the plasma concentration-time curve from time zero to 
24 hours (AUC0-24h) will be calculated using the linear trapezoidal rule.  Apparent systemic 
(plasma) clearance after SC administration (CL0-24h /F) will be calculated from  
CL0-24h/F = Actual Dose/AUC0-24h.  Mean residence time (MRT) from time zero to 24 hours after 
the SC administration will be calculated from the equation,  
MRT0-24h = AUMC0-24h/AUC0-24h, where AUMC0-24h is the area under the moment plasma 
concentration-time curve from time zero to 24 hours after the SC administration.  Other PK 
parameters, as appropriate, may be determined or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics by treatment group and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 


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treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the last ADA sample 
collection day, and subject - peak titer if applicable, will be listed by their prior treatment in 
Study ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by treatment group.  Furthermore, onset and titer of the ADA 
response, if applicable, will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 


ISIS 304801-CS7 
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as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 


ISIS 304801-CS7 
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68 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
 
 


ISIS 304801-CS7 
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69 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 


ISIS 304801-CS7 
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13. 
REFERENCES 
Altmann KH, Fabbrot D, Dean NM, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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18 November 2016 
 
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Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


ISIS 304801-CS7 
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14. 
APPENDICES 
 
 
 


ISIS 304801-CS7 
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Amendment 6 
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18 November 2016 
 
73 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
 


ISIS 304801-CS7 
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Amendment 6 
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74 
Appendix A Schedule of Procedures 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-8 to -2 
-2 to 
 -1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 
11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
Xl 
Xl 
X 
Xl 
Xl 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Physical Examination 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Blood Draw (Fasting)d 
Chemistry Panel 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC with Differentialc 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Sedimentation Rate 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Troponin I 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Platelet Bound Autoantibodiese 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK - Volanesorsen 
 
 
Xn 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
FSH (women only, if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testf 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Archived Serum & Plasma 
Samplesg 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 


ISIS 304801-CS7 
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Amendment 6 
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18 November 2016 
 
75 
Appendix A Schedule of Procedures Continued 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-8 to -2 
-2 to -
1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 Wk 28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Urinalysisd 
X 
X 
Xo 
 
 
X 
 
X 
 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
 
Xo 
 
Xo 
 
 
Xo 
 
Xo 
Xo 
Fundus Photographyh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Genetic testing for FCS diagnosis (if 
not available in medical history)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Food/Drink Diary (quarterly)j 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Diet/Alcohol Counselingk 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Screening and Qualification (Group 3) procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Patient charts will be reviewed in order to collect data for events of acute pancreatitis or suspected pancreatitis in the patient’s medical history.  Chart review 
may be conducted at any time during the study.  These events will be adjudicated in the same manner as for events of pancreatitis during the study 
c 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1 week and determined not to have met a stopping rule before dosing can continue.  If there is no reportable platelet count within 14 days of the last 
platelet count, the Investigator will contact the patient to hold dosing until a new platelet count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that 
the patient could be approaching the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
18 November 2016 
 
76 
Appendix A Schedule of Procedures Continued 
Legend Text Continued 
d 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
e 
May be done 
f 
Females of childbearing potential only 
g 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
h 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 [ISIS 304801-CS16 roll-over patients] and 
Group 3) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
i 
Genetic testing can be conducted for study qualification (Group 2 [ISIS 304801-CS16 roll-over patients] and Group 3); genetic testing will only be conducted if 
allowed in the geographic region and only after the patient has given specific written informed consent for genetic testing 
j 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
k 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
l 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
m 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
n 
Full or abbreviated PK profile (see Appendix C) 
o 
Expanded urinalysis (see Appendix B) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
18 November 2016 
 
77 
Appendix A Schedule of Procedures – Extended Treatment Period 
Study Period 
Treatment Period 
Post-Treatment 
Follow-up 
Study Week 
Wk 54 
& 56 
Wk 
58 
Wk 60 
& 62 
Mo 15 
Wk 64 
Wk 66 
& 68 
Wk 
70 
Wk 72 
& 74 
Mo 18 
Wk 76 
Wk 78 
& 80 
Wk 
82 
Wk 84, 
86, & 88 
Mo 21 
Wk 90 
Wk 92 
& 94 
Wk 
96 
Wk 98, 
100 & 
102 
Mo 24 
Wk 
104 
Wk 
106 
& 
108 
Wk 
110 
Mo 27 
Wk 117 
Study Day 
372 & 
386 
400 414 & 
428  
442 
456 & 
470 
484 498 & 
512 
526 
540 & 
554 
568 582, 596 
& 610 
624 
638 & 
652 
666 
680, 
694 & 
708 
722 
736  
& 
750 
764 
813 
Visit Window+/- Days 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Outpatient Visit 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
Xf 
X 
Xf 
Xf 
X 
Vital Signs (+ body weight) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis(including P/C ratio) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood Draw (Fasting)b 
Chemistry Panel 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CBC with Differentiala 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Troponin I 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 304801c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-ISIS 304801 Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Serum Pregnancy Testd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Weekly Study Drug: SC Injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diet/Alcohol Counselinge 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
18 November 2016 
 
78 
Appendix A Schedule of Procedures – Extended Treatment Period Continued 
Legend Text 
a 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1 week and determined not to have met a stopping rule before dosing can continue.  If there is no reportable platelet count within 14 days of the last 
platelet count, the Investigator will contact the patient to hold dosing until a new platelet count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that 
the patient could be approaching the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 
b 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration. 
c 
Abbreviated PK collection (see Appendix C) 
d 
Females of childbearing potential only 
e 
To reinforce compliance to the diet and alcohol restrictions 
f 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
79 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
80 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Screening Tests (Group 3) 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (women only) 
• 
Serum βhCG (women 
only) 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
Troponin I2 
• 
CK-MB2 
• 
Platelet Bound 
Autoantibodies3 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination4 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
3 
May be done 
4 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
81 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
82 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65# 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
# 
Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
 
PK Sampling Schedule (Extended Treatment Period) 
Week 
Wk 
76 
Wk 
104 
Wk 
117 
Study Day 
D526 
D722 
D813 
Visit Window 
+/- Days 
2 
2 
7 
Time Point 
Pre-dose,  
Pre-dose 
Anytime 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
83 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
84 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
85 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol 
18 November 2016 
 
86 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
Adverse Event 
Mild 
Moderate 
Severe 
Urine 
Proteinuria 
Adults 
1 + proteinuria; 
2+ proteinuria; 
Urinary protein 
g/24 hrs; 
urinary protein < 1.0 g/24 hrs 
urinary protein 1.0 - 3.4 g/24 hrs; 
Children 
-
Urine PIC (Protein/Creatinine) 
Urine P/C >1.9 
ratio 0.5 - 1.9 
Gross hematuria; transfusion, 
Asymptomatic; clinical or diagnostic 
IV medications or 
Symptomatic; urinary catheter or hospitalization indicated; 
Hematuria 
observations only; intervention not 
bladder irrigation indicated 
elective endoscopic, radiologic 
indicated 
or operative intervention 
indicated 
tGrading for this parameter is derived from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept 2007 
*Grading for this parameter is derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, Nov 2014 
tModified for consistency with the ADA and Endocrine Society Guidelines (Seaquist ER, Anderson J, Childs B, et al. 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. 
Diabetes Care 2013;36: 1384-95) 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 6 - France – 16 September 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 30480 l-CS7 
Protocol - France 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 6 
16 September 2016 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 6- France- 16 September 2016 
Protocol History: 
Original Protocol: 
Protocol Amendment 1: 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Protocol Amendment 5: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 2010 
MD, MBA 
28 August 2015 
2 February 2016 
22 April 2016 
9 May 2016 
6 June 2016 
19 August 2016 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 6 - France 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
, Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
16 September 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 6 - France 
Date:  
 
16 September 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 16 September 2016, and agree to conduct the study 
as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................13 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................19 
STUDY GLOSSARY ...................................................................................................................20 
1. 
OBJECTIVES .....................................................................................................................22 
2. 
BACKGROUND AND RATIONALE ..............................................................................22 
2.1 
Overview of Disease ......................................................................................................22 
2.2 
Therapeutic Rationale ....................................................................................................23 
2.3 
Volanesorsen ..................................................................................................................24 
2.3.1 
Mechanism of Action .............................................................................................24 
2.3.2 
Chemistry ...............................................................................................................25 
2.3.3 
Preclinical Experience ............................................................................................26 
2.3.4 
Clinical Experience ................................................................................................27 
2.4 
Rationale for Dose and Schedule of Administration .....................................................28 
3. 
EXPERIMENTAL PLAN ..................................................................................................29 
3.1 
Study Design ..................................................................................................................29 
3.2 
Number of Study Centers ..............................................................................................29 
3.3 
Number of Patients ........................................................................................................29 
3.4 
Overall Study Duration and Follow-up .........................................................................29 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification ....................................................................................29 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification29 
3.4.3 
Treatment ................................................................................................................29 
3.4.4 
Post-Treatment .......................................................................................................30 
3.5 
End-of-Study ..................................................................................................................30 
3.6 
Data and Safety Monitoring Board ................................................................................30 
4. 
PATIENT ENROLLMENT ...............................................................................................30 
4.1 
Screening/Qualification .................................................................................................30 
4.2 
Enrollment .....................................................................................................................31 
5. 
PATIENT ELIGIBILITY ..................................................................................................31 
5.1 
Inclusion Criteria ...........................................................................................................31 
5.2 
Exclusion Criteria ..........................................................................................................32 
6. 
STUDY PROCEDURES ....................................................................................................34 
6.1 
Study Schedule ..............................................................................................................34 
6.1.1 
Qualification (Groups 1 and 2) ...............................................................................35 
6.1.2 
Screening and Qualification (Group 3) ..................................................................35 
6.1.3 
Treatment Period ....................................................................................................35 
6.1.4 
Pharmacokinetic (PK) Subgroup ............................................................................35 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
6 
6.1.5 
Post-Treatment Period ............................................................................................36 
6.2 
Additional Study Assessments .......................................................................................36 
6.2.1 
Laboratory Assessments .........................................................................................36 
6.2.2 
Physical Exams and Vital Signs .............................................................................36 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................37 
6.2.2.2 
Lipemia Retinalis .............................................................................................37 
6.2.3 
Echocardiography ...................................................................................................37 
6.2.4 
ECG ........................................................................................................................37 
6.2.5 
MRI ........................................................................................................................37 
6.2.6 
Quality of Life Assessments ...................................................................................37 
6.2.7 
Disease Symptom Diary .........................................................................................37 
6.2.8 
Diet Monitoring ......................................................................................................37 
6.2.9 
Family History ........................................................................................................38 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................38 
6.3.1 
Contraception Requirements ..................................................................................38 
6.3.2 
Other Requirements ................................................................................................39 
7. 
STUDY DRUG ....................................................................................................................39 
7.1 
Volanesorsen Description ..............................................................................................39 
7.2 
Packaging and Labeling .................................................................................................40 
7.3 
Study Drug Accountability ............................................................................................40 
8. 
TREATMENT OF PATIENTS .........................................................................................40 
8.1 
Volanesorsen Administration ........................................................................................40 
8.2 
Other Protocol-Required Drugs .....................................................................................40 
8.3 
Other Protocol-Required Treatment Procedures ............................................................41 
8.4 
Treatment Precautions ...................................................................................................41 
8.5 
Safety Monitoring Rules ................................................................................................41 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................41 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................42 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................42 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................43 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................43 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........43 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................44 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................44 
8.5.9 
Acute Pancreatitis ...................................................................................................45 
8.6 
Stopping Rules ...............................................................................................................45 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................46 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................46 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................46 
8.7 
Adjustment of Dose Frequency .....................................................................................49 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
7 
8.8 
Discontinuation of Study Treatment ..............................................................................49 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................49 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .50 
8.9 
Withdrawal of Patients from the Study ..........................................................................50 
8.10 
Concomitant Therapy and Procedures ...........................................................................50 
8.10.1 
Concomitant Therapy .............................................................................................51 
8.10.2 
Concomitant Procedures .........................................................................................51 
8.11 
Treatment Compliance ...................................................................................................51 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................51 
9.1 
Sponsor Review of Safety Information .........................................................................51 
9.2 
Regulatory Requirements ..............................................................................................52 
9.3 
Definitions .....................................................................................................................52 
9.3.1 
Adverse Event ........................................................................................................52 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................53 
9.3.3 
Serious Adverse Event (SAE) ................................................................................53 
9.4 
Monitoring and Recording Adverse Events ...................................................................53 
9.4.1 
Serious Adverse Events ..........................................................................................54 
9.4.2 
Non-Serious Adverse Events ..................................................................................54 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................54 
9.4.3.1 
Relationship to the Study Drug ........................................................................54 
9.4.3.2 
Severity ............................................................................................................55 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................55 
9.4.3.4 
Treatment Given for Adverse Event ................................................................55 
9.4.3.5 
Outcome of the Adverse Event ........................................................................55 
9.4.4 
Adjudication Committees .......................................................................................56 
9.5 
Procedures for Handling Special Situations ..................................................................56 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................56 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............56 
9.5.3 
Dosing Errors .........................................................................................................57 
9.5.4 
Contraception and Pregnancy .................................................................................57 
10. STATISTICAL CONSIDERATIONS ..............................................................................58 
10.1 
Study Endpoints .............................................................................................................58 
10.1.1 
Efficacy Endpoints .................................................................................................58 
10.1.2 
Safety Endpoints .....................................................................................................58 
10.2 
Sample Size ....................................................................................................................58 
10.3 
Populations .....................................................................................................................59 
10.4 
Definition of Baseline ....................................................................................................59 
10.5 
Interim Analysis .............................................................................................................59 
10.6 
Planned Methods of Analysis ........................................................................................59 
10.6.1 
Demographic and Baseline Characteristics ............................................................60 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
8 
10.6.2 
Safety Analysis .......................................................................................................60 
10.6.3 
Efficacy Analysis ...................................................................................................60 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................61 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................61 
10.6.4.2 
Immunogenicity Analysis ................................................................................61 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................62 
11.1 
Informed Consent ..........................................................................................................62 
11.2 
Ethical Conduct of the Study .........................................................................................63 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................63 
11.4 
Patient Confidentiality ...................................................................................................63 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................64 
12.1 
Protocol Amendments ....................................................................................................64 
12.2 
Study Termination .........................................................................................................64 
12.3 
Study Documentation and Storage ................................................................................64 
12.4 
Study Monitoring ...........................................................................................................65 
12.5 
Language ........................................................................................................................65 
12.6 
Compensation for Injury ................................................................................................65 
13. REFERENCES ....................................................................................................................66 
14. APPENDICES .....................................................................................................................68 
Appendix A 
Schedule of Procedures ....................................................................................69 
Appendix B 
List of Laboratory Analytes .............................................................................75 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................77 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......79 
 
TABLE OF TABLES 
Page 
Table 1 Volanesorsen (ISIS 304801) Characteristics ................................................................ 40 
Table 2 Actions in Patients With Low Platelet Count ............................................................... 48 
Table 3 Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence ................................................................................................. 52 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 23 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 25 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 27 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 6
Protocol - France 
 
16 September 2016
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
6 - France 
Amendment Date: 
16 September 2016 
 
The purpose of this protocol amendment is to incorporate changes requested by ANSM as part of 
the conditional approval of the study, dated 7 September 2016.  As such, the following 
modifications to Protocol ISIS 304801-CS7 Amendment 5 dated 19 August 2016 have been 
made: 
1. In order to reduce the unlikely but potential increased risk of pancreatitis during the 
period of corticosteroid therapy, triglyceride levels will be monitored weekly during 
corticosteroid treatment and the laboratory alert will be changed from 2,000 to 
500 mg/dL during this period. 
2. To increase the post-treatment follow-up period from 13 weeks to 26 weeks or longer, if 
needed, until apoC-III levels return to baseline values. 
In addition, language was added to indicate that after completion of the Week 52 visit 
assessments, patients will enter the at least 26-week post-treatment evaluation period or will 
participate in an expanded access program pending approval by the IRBs/IEC, and the 
appropriate regulatory authorities. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design.  
The following table provides a summary list of major changes to the protocol: 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis: 
Study Design 
Protocol Synopsis:  
Study Visit 
Schedule and 
Procedures 
3.1  Study Design 
Was: 
Following the Week 52 visit, patients will enter a 13-week post-
treatment evaluation period. 
 
Is: 
Following the Week 52 visit, patients will enter an at least 
26-week post-treatment evaluation period or will participate in 
an expanded access program pending approval by the 
IRBs/IEC, and the appropriate regulatory authorities. 
To follow guidance provided 
by the ANSM to extend the 
post-treatment follow-up 
period until apoC-III levels 
return to baseline values 
To provide an expanded 
access program as an option 
for patients that may be 
benefiting from active drug 
treatment 
Protocol Synopsis: 
Study Population 
5.1  Inclusion 
Criteria 
Was: 
4. 
Able and willing to participate in a 65-week study 
 
Is: 
4. 
Able and willing to participate in a 78-week study 
To follow guidance provided 
by the ANSM to extend the 
post-treatment follow-up 
period until apoC-III levels 
return to baseline values 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
10 
Protocol Section 
Description of Change 
Rationale 
Study Design and 
Treatment Schema 
Appendix A  
Schedule of 
Procedures 
Was: 
 
Study Period 
Post Treatment 
Follow-up 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Study Day 
372 
& 
386 
400 449 
Visit Window+/- Days 
2 
7 
7 
Informed Consent 
 
 
 
Outpatient Visit 
Xj 
Xj 
X 
Inclusion/Exclusion Criteria 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
Physical Examination 
 
 
X 
12- lead ECG (triplicate) 
 
 
X 
MRI (liver/spleen) 
 
 
 
Echocardiography 
 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
 
X 
X 
CBC with Differentialb 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
Coagulation (aPTT, PT, 
INR) 
 
 
 
hsCRP, HbA1c, FPG, 
and de-lipidated free 
glycerol 
 
 
X 
Sedimentation Rate 
 
 
X 
Complement (C5a, Bb) 
 
 
X 
Plasma PK - 
Volanesorsen 
 
 
X 
Anti-Volanesorsen 
Antibodies 
 
 
X 
FSH (women only, if 
applicable) 
 
 
 
Serum Pregnancy Testd 
 
X 
X 
Archived Serum & 
Plasma Samplese 
 
 
X 
Troponin Io 
 
 
 
Urinalysisc 
 
X
m 
X
m 
Fundus Photographyf 
 
 
 
Genetic testing for FCS 
diagnosis (if not available in 
medical history)g 
 
 
 
Weekly Study Drug:  SC 
Injection 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
Quality of Life 
Assessment(s) 
 
 
X 
Food/Drink Diary 
(quarterly)h 
 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
Adverse Events 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
To follow guidance provided 
by the ANSM to extend the 
post-treatment follow-up 
period until apoC-III levels 
return to baseline values 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 6
Protocol - France 
 
16 September 2016
 
11 
Protocol Section 
Description of Change 
Rationale 
Study Design and 
Treatment Schema 
Appendix A 
Schedule of 
Procedures 
Continued 
Is: 
 
Study Period 
Post Treatment Follow-up
p
Study Week 
Wk 
54
&
56 
Wk
58 
Wk
65 
Wk
71 
Wk
78 
Study Day 
372
&
386
400
449
49
1 
540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Informed Consent 
 
 
 
 
 
Outpatient Visit 
X
j 
X
j 
X 
X
j 
X 
Inclusion/Exclusion Criteria 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
Echocardiography 
 
 
 
 
 
Blood Draw (Fasting)
c 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differential
b 
X 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
Coagulation (aPTT, PT, 
INR) 
 
 
 
 
 
hsCRP, HbA1c, FPG, 
and de-lipidated free 
glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb)
 
 
X 
 
X 
Plasma PK - 
Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen 
Antibodies 
 
 
X 
 
X 
FSH (women only, if 
applicable) 
 
 
 
 
 
Serum Pregnancy Test
d
 
X 
X 
X 
X 
Archived Serum & 
Plasma Samples
e 
 
 
X 
 
X 
Troponin I
o 
 
 
 
 
 
Urinalysis
c 
 
X
m 
X
m 
X
m 
X
m 
Fundus Photography
f 
 
 
 
 
 
Genetic testing for FCS 
diagnosis (if not available in 
medical history)
g 
 
 
 
 
 
Weekly Study Drug:  SC 
Injection 
 
 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life 
Assessment(s) 
 
 
X 
 
X 
Food/Drink Diary 
(quarterly)
h 
 
 
X 
 
X 
Diet/Alcohol Counseling
i 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
p  If needed, the post-treatment follow-up period will be 
extended (with patients monitored every 6 weeks) until 
apoC-III levels return to baseline values 
To follow guidance provided 
by the ANSM to extend the 
post-treatment follow-up 
period until apoC-III levels 
return to baseline values 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 6
Protocol - France 
 
16 September 2016
 
12 
Protocol Section 
Description of Change 
Rationale 
3.4.4  Post-
Treatment 
6.1.5  Post-
Treatment Period 
Was: 
After completion of the Week-52 visit assessments, patients 
will enter the 13-week post-treatment evaluation period.  This 
period consists of 4 Study Center visits on Weeks 54, 56, and 
58 (which may be conducted by a home healthcare nurse), 
and Week 65 as outlined in the Schedule of Procedures in 
Appendix A. 
 
Is: 
After completion of the Week 52 visit assessments, patients 
will enter the at least 26-week post-treatment evaluation period 
or will participate in an expanded access program pending 
approval by the IRBs/IEC, and the appropriate regulatory 
authorities.  The 26-week period consists of at least 6 Study 
Center visits on Weeks 54, 56, 58, 65, 71, and 78 (Weeks 54, 
56, 58, and 71 may be conducted by a home healthcare 
nurse), as outlined in the Schedule of Procedures in 
Appendix A. 
To follow guidance provided 
by the ANSM to extend the 
post-treatment follow-up 
period until apoC-III levels 
return to baseline values 
To provide an expanded 
access program as an option 
for patients that may be 
benefiting from active drug 
treatment 
For consistency with the above changes, Week 78 was added to the following sections: 
6.2.4  ECG 
6.2.6  Quality of Life Assessments 
6.2.8  Diet Monitoring 
8.8.1  Follow-up Visits for Early Termination from Treatment Period 
8.8.2  Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
8.10.2  Concomitant Procedures 
9.4.1  Serious Adverse Events 
9.4.2  Non-Serious Adverse Events 
Appendix C  Pharmacokinetic Sampling Schedule 
8.6.3  Stopping 
Rules for Platelet 
Count Results 
Table 2  Actions in 
Patients with Low 
Platelet Count 
Was: 
Administration of steroids is recommended for patients whose 
platelet count is less than 25,000/mm3.  Recovery in platelet count 
may be accelerated by administration of high dose steroids.  
Treatment guidelines for immune thrombocytopenia (Provan et al. 
2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 
2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 
7 days (note:  may require continuation with oral steroids after 
methylprednisolone). 
 
Is: 
Administration of steroids is recommended for patients whose 
platelet count is less than 25,000/mm3.  Recovery in platelet count 
may be accelerated by administration of high dose steroids.  
Treatment guidelines for immune thrombocytopenia (Provan et al. 
2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 
2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 
7 days (note:  may require continuation with oral steroids after 
methylprednisolone).  In order to reduce the unlikely but potential 
increased risk of pancreatitis during the period of corticosteroid 
therapy, triglyceride levels will be monitored weekly during 
corticosteroid treatment and the laboratory alert will be changed 
from an increase of 2,000 to 500 mg/dL during that period. 
To follow guidance 
provided by the ANSM to 
clarify the additional 
patient safety regarding 
monitoring of triglyceride 
levels 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
13 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will enter an at least 
26-week post-treatment evaluation period or will participate in an expanded 
access program pending approval by the IRBs/IEC, and the appropriate 
regulatory authorities. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order 
to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for 
the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label 
study  
4. 
Able and willing to participate in a 78-week study 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
14 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and FSH levels in the 
postmenopausal range for the laboratory involved), abstinent*, or if 
engaged in sexual relations of child-bearing potential, patient is 
using an acceptable contraceptive method (refer to Section 6.3.1) 
from time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening* 
b. HbA1c ≥ 9.0% at Screening* 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage 
or addition of new medication within 12 weeks of screening* [with the 
exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to screening* 
4. History within 6 months of screening* of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of screening* 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
15 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria Continued 
5. Any of the following laboratory values at Screening* 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Screening* 
d. 
LDL-C > 130 mg/dL at Screening* 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding 
diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Screening* 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully 
treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1-month of screening*, or 5 half-lives of investigational agent, 
whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
16 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria Continued 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to screening* and dose 
and regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
screening* 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
screening* unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to screening* and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to screening* and dose and regimen expected to remain 
constant during the treatment period 
f. Glybera gene therapy within 2 years prior to screening* 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening* and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening* and dose and regimen expected to 
remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to screening* or planned 
during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to 
screening* (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening* or of 
> 499 mL within 60 days of screening* 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, including new or worsening of existing 
condition, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the 
patient participating in or completing the study 
*(Group 3) or Qualification (Groups 1 and 2) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
17 
PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up to 
2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A 
• 
Group 3 patients (did not participate in an index study):  An up to 
8-week screening and qualification period, including a diet 
stabilization period of at least 6 weeks (screening and diet 
stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease 
management prior to screening).  Please refer to Section 6.1.2 and 
Appendix A 
• 
All patients: 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
An at least 26-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter an at least 26-week post-
treatment evaluation period or will participate in an expanded access program 
pending approval by the IRBs/IEC, and the appropriate regulatory authorities. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
18 
PROTOCOL SYNOPSIS Continued 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
SCREENING PERIOD 
Weeks -8 to -2 (Group 3 patients only) 
QUALIFICATION 
PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 78* 
Safety, efficacy, PK and PD assessments 
* If needed, the post-treatment follow-up 
period will be extended (with patients 
monitored every 6 weeks) until apoC-III 
levels return to baseline values 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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STUDY GLOSSARY Continued 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the 
RNase H1-mediated degradation of the apoC-III mRNA, thus preventing production of the 
apoC-III protein.  Maximal antisense-mediated reduction of target mRNA levels is typically 
greater than 90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 
2010).  Furthermore, reduction in target mRNA levels using this approach correlates directly 
with a subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or  
ISIS 304801-CS16 index studies 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter an at least 26-week post-treatment evaluation period 
or will participate in an expanded access program pending approval by the IRBs/IEC, and the 
appropriate regulatory authorities. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification 
A period of up to 2 weeks (unless approved by the Sponsor) is given to complete qualification 
assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and Appendix A. 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification 
An up to 8-week screening and qualification period, including a diet stabilization period of at 
least 6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if 
the patient is following a diet for optimal control of TGs and disease management prior to 
screening.  Please refer to Section 6.1.2 and Appendix A. 
3.4.3 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 


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3.4.4 
Post-Treatment 
The post-treatment evaluation period is at least 26 weeks and consists of at least 6 Study Center 
visits on Weeks 54, 56, 58, 65, 71, and 78 (Weeks 54, 56, 58, and 71 may be conducted by a 
home healthcare nurse). 
3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Screening/Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open-label study are performed.   
Groups 1 and 2 (Qualification):  During the qualification period, the eligibility of the patient to 
enroll in the open-label study will be determined.  Final assessments from the ISIS 304801-CS6 
or ISIS 304801-CS16 studies may be used for qualification.  A period of up to 2 weeks after 
completion of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the 
Sponsor) is given to complete qualification.  Qualified patients will retain the unique patient 
identification number that was assigned to them during the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies.  The patient identification number will be used to identify the 
patient throughout the extension trial and must be used on all study documentation related to that 
patient.  The patient identification number must remain constant throughout the extension trial. 
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered 
enrolled into the study and will be assigned a unique screening number before any study 
procedures, including screening procedures, are performed.  At the time of enrollment, patients 
will be assigned a unique patient identification number.  This number will be used to identify the 
patient throughout the trial and must be used on all study documentation related to that patient.  
The screening number and patient identification number must remain constant throughout the 
entire trial.  In the event the patient is re-consented and re-screened the patient must be given a 
new screening number.  Screening numbers and patient identification numbers, once assigned, 
will not be re-used. 


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4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all Screening (Group3) and 
qualification assessments have been completed and after the Investigator has verified that they 
are eligible per criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to 
enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order to enter into the 
open-label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
c. Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the  
 
ISIS 304801-CS16 index study 
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label study 
4. Able and willing to participate in a 78-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 


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medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening* 
b. HbA1c ≥ 9.0% at Screening* 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of screening* [with the exception of ± 10 units of 
insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening* 
4. History within 6 months of screening* of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack 
or unstable congestive cardiac failure requiring a change in medication or major surgery 
within 3 months of screening* 
5. Any of the following laboratory values at Screening* 
a. Hepatic: 
• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• ALT > 2.0 x ULN 


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• AST > 2.0 x ULN 
b. Renal: 
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick.  In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs 
• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick.  In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field 
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Screening* 
d. LDL-C > 130 mg/dL at Screening* 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding diathesis or 
coagulopathy or clinically-significant abnormality in coagulation parameters at 
Screening* 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1-month 
of screening*, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable 
dose for at least 3 months prior to screening* and dose and regimen expected to 


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remain constant during the treatment period.  Patients taking OTC omega-3 fatty 
acids should make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening* 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening* 
unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to screening* and dose and regimen expected to 
remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
screening* and dose and regimen expected to remain constant during the treatment 
period 
f. Glybera gene therapy within 2 years prior to screening* 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to screening* and regular clinical monitoring is 
performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to screening* and dose and regimen expected to remain constant during the treatment 
period 
i. Plasma apheresis within 4 weeks prior to screening* or planned during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening* (Occasional 
or intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening* or of > 499 mL within 
60 days of screening* 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or 
placebo) 
17. Have any other conditions, including new or worsening of existing condition, which, in 
the opinion of the Investigator or the Sponsor would make the patient unsuitable for 
inclusion, or could interfere with the patient participating in or completing the study 
*(Group 3) or Qualification (Groups 1 and 2) 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 


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6.1.1 
Qualification (Groups 1 and 2) 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  An 8-week period, including a diet stabilization period of at least 
6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease management prior to screening) 
is given to perform the screening evaluations.  The qualification assessments will be performed 
at Week -2 to -1, ideally after patient eligibility has been determined, and on Study Day 1.  
Abnormal screening results may be retested for review by the Study Medical Monitor for 
eligibility purposes 
6.1.3 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 2.5, 
4, 6, 8, 10, 12, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 40, 42, 44, 46, 48, and 50 may be 
conducted by a home healthcare nurse.  Approval for study procedures to be conducted by a 
home healthcare nurse on other outpatient visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples and samples drawn locally should also 
be sent to the central laboratory for analysis whenever possible.  Every effort should be made to 
ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  Dosing 
instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.4 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 


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Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.5 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the at least 26-week 
post-treatment evaluation period or will participate in an expanded access program pending 
approval by the IRBs/IEC, and the appropriate regulatory authorities.  The 26-week period 
consists of at least 6 Study Center visits on Weeks 54, 56, 58, 65, 71, and 78 (Weeks 54, 56, 58, 
and 71 may be conducted by a home healthcare nurse), as outlined in the Schedule of Procedures 
in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and determined not to have met a stopping rule before dosing 
can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to ensure that the count 
has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 


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always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 rollover patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, 
Week 65, and Week 78. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, Week 65, and Week 78. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 


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1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, Week 65, and Week 78. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent† or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 


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intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
* Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
† Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 
 
 


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Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 


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8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 


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In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 2 in Section 8.6.3. 
Additional lab tests will be determined by the Sponsor Medical Monitor or designee in 
consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 


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parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 


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8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1-week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
 
 


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The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 


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8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 2 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a rate of decline ≥ 50% between two 
consecutive assessments, irrespective of the platelet level, then dosing of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored daily until 
2 successive values show improvement then monitored every 2-3 days until platelet count is 
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Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note:  may require continuation with oral steroids after methylprednisolone).  In order to reduce 
the unlikely but potential increased risk of pancreatitis during the period of corticosteroid 
therapy, triglyceride levels will be monitored weekly during corticosteroid treatment and the 
laboratory alert will be changed from an increase of 2,000 to 500 mg/dL during that period. 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks or a reduced dose of 150 mg per week (refer to Section 8.7).  The suitability of the 
patient for continued dosing will be determined by the Investigator in consultation with the Study 
Medical Monitor and will be based on factors such as the original rate of decline in the patient’s 
platelet count, whether any bleeding events were experienced by the patient, and the speed of 
recovery of platelet count upon holding of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Following a rechallenge platelet count should be tested every week until count is stable. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 


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4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
Table 2 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every 1-week until stable* 
75K-100K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 1-week 
50K-75K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 or a rate of 
decline ≥ 50% between 
two consecutive 
assessments, irrespective of 
the platelet level 
Permanently discontinue Study Drug   
Closer observation 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
< 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended** 
Consider need for hospitalization 
and referral to hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
At least 3 consecutive values measured weekly that are stable as determined by the Sponsor Medical Monitor 
and > 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methyl prednisolone).  In order 
to reduce the unlikely but potential increased risk of pancreatitis during the period of corticosteroid therapy, 
triglyceride levels will be monitored weekly during corticosteroid treatment and the laboratory alert will be 
changed from an increase of 2,000 to 500 mg/dL during that period. 


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8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 2 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 
schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in Table 2 in Section 8.6.3 for the first 6 weeks after 
discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3), the next platelet count should be taken within at least 6 weeks so that patients 
are monitored for at least 12 weeks after discontinuing Study Drug.  Patients should also be 
strongly encouraged to attend applicable landmark visits at Weeks 12, 13, 25, 26, and 50, 52 
(calculated based on the time elapsed since Day 1) to collect fasting lipid panels and conduct 
safety assessments in accordance with the Schedule of Procedures in Appendix A.  Any patient 
who discontinues treatment after Week 44 should also be strongly encouraged to attend a final 
follow-up visit (Week 78 visit assessments) approximately 26 weeks after their last dose of 
Study Drug, in addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 


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8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 2 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 
6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  
Patients should also be encouraged to undergo a final follow-up visit (Week 78, see Appendix A) 
prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 


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8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 78 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 


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9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 3 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 


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study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 


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9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 78 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 78 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 


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9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 


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• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 


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• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
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Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 


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10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 evaluable PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline for safety will be the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 
will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 
All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 


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10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
studies.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index studies. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index studies, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index studies. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index studies. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index studies. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index studies.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index studies for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 


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The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group of the index studies. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification for Group 1 and 2 patients by their 
prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 2 
patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the index 
study (and all patients in Group 3) will receive the first treatment of volanesorsen (single-dose 
PK), while patients who received volanesorsen in the index studies had been on volanesorsen 
treatment for 12 months (ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data 
collected from these patients reflect steady-state PK.  The maximum observed drug 
concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  Area under the plasma concentration-time curve from time zero to 
24 hours (AUC0-24hr) will be calculated using the linear trapezoidal rule.  Apparent systemic 
(plasma) clearance after SC administration (CL0-24hr /F0-24hr) will be calculated from  
CL0-24hr /F0-24hr = Actual Dose/AUC0-24hr.  Mean residence time (MRT) from time zero to 
24 hours after the SC administration will be calculated from the equation,  
MRT0-24hr = AUMC0-24hr /AUC0-24hr, where AUMC0-24hr is the area under the moment plasma 
concentration-time curve from time zero to 24 hours after the SC administration.  Other PK 
parameters, as appropriate, may be determined or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 


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listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the duration of ADA 
response (number of days between Tfirst and Tlast) if appropriate, the last ADA sample collection 
day, and subject - peak titer if applicable, will be listed by their prior treatment in Study 
ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16.  Furthermore, onset, duration, and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., %change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
 
 


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11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 


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No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 


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13. 
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Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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16 September 2016 
 
67 
Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
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Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
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Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
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Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
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with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
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ISIS 304801-CS7 
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14. 
APPENDICES 
 
 
 


ISIS 304801-CS7 
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16 September 2016 
 
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Appendix A 
Schedule of Procedures 
 
Screen/Run In through Treatment Period 
Post-Treatment Follow-up 
 


ISIS 304801-CS7 
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16 September 2016 
 
70 
Appendix A Schedule of Procedures – Screen/Run In through Treatment Period 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Study Week 
-8 to -2 
-2 to -
1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Physical Examination 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
Xk 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
CBC with Differentialb 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Coagulation (aPTT, PT, INR) 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
Xn 
Xn 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Sedimentation Rate 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Plasma PK - Volanesorsen 
 
 
Xl 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
FSH (women only, if applicable) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Archived Serum & Plasma 
Samplese 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Troponin Io 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
71 
Appendix A Schedule of Procedures - Screen/Run In through Treatment Period Continued 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Study Week 
-8 to -2 
-2 to -
1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
Visit Window+/- Days 
0 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Urinalysisc 
X 
X 
Xm 
 
 
X 
 
X 
 
 
Xm 
 
Xm 
 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
Genetic testing for FCS diagnosis (if 
not available in medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Diary (weekly) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Diet/Alcohol Counselingi 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


ISIS 304801-CS7 
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Amendment 6 
Protocol - France 
16 September 2016 
 
72 
Appendix A Schedule of Procedures – Post-Treatment Follow-up  
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Informed Consent 
 
 
 
 
 
Outpatient Visit 
Xj 
Xj 
X 
Xj 
X 
Inclusion/Exclusion Criteria 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
 
 
X 
 
X 
Physical Examination 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
Echocardiography 
 
 
 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
 
X 
X 
X 
X 
CBC with Differentialb 
X 
X 
X 
X 
X 
Serum Lipid Panel 
 
 
X 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
 
X 
 
X 
Sedimentation Rate 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
Serum Pregnancy Testd 
 
X 
X 
X 
X 
Archived Serum & Plasma Samplese 
 
 
X 
 
X 
Troponin Io 
 
 
 
 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
73 
Appendix A Schedule of Procedures – Post-Treatment Follow-up Continued 
Study Period 
Post Treatment Follow-upp 
Study Week 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
71 
Wk 
78 
Study Day 
372 
& 
386 
400 
449 
491 
540 
Visit Window+/- Days 
2 
7 
7 
7 
7 
Urinalysisc 
 
Xm 
Xm 
Xm 
Xm 
Fundus Photographyf 
 
 
 
 
 
Genetic testing for FCS diagnosis 
(if not available in medical 
history)g 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
 
X 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
X 
Diet/Alcohol Counselingi 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
74 
Appendix A Schedule of Procedures Continued 
a 
Screening (Group 3) and Qualification procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should 
be collected in parallel and analyzed locally. In the event that both the central and local sample are unreportable 
(e.g., due to hemolyzed or clumped blood samples) another sample must be repeated within 1-week and 
determined not to have met a stopping rule before dosing can continue.  If there is no reportable platelet count 
within 14 days of the last platelet count, the Investigator will contact the patient to hold dosing until a new platelet 
count is obtained and reviewed.  All platelet count results will be promptly reviewed by the Investigator to ensure 
that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3.  In the event of any platelet count less than 
50,000/mm3 or a rate of decline ≥ 50% between two consecutive assessments, irrespective of the platelet level, 
then dosing of a patient with Study Drug (ISIS 304801 or placebo) will be stopped permanently.  Any case of a 
platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  
During treatment period urine and blood samples will be collected prior to Study Drug administration.  Does not 
apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or 
adverse events (e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of 
kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug 
(Group 2 [ISIS 304801-CS16 rollover patients] and Group 3) and repeated at Week 52 (Please refer to 
Section 6.2.2.2) 
g 
Genetic testing can be conducted for study qualification (Group 2 [ISIS 304801-CS16 rollover patients] and 
Group 3); genetic testing will only be conducted if allowed in the geographic region and only after the patient has 
given specific written informed consent for genetic testing 
h 
In addition to diary, patients will be contacted at random times during the study to review their current eating and 
drinking habits 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will 
also be performed by dietician or study personnel 
j 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as 
arranged by the Study Center personnel 
k 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
l 
Full or abbreviated PK profile (see Appendix C) 
m 
Expanded urinalysis (see Appendix B) 
n 
HbA1c only 
o 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
p 
If needed, the post-treatment follow-up period will be extended (with patients monitored every 6 weeks) until 
apoC-III levels return to baseline values 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
75 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
76 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
77 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
78 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose Pre-dose Pre-dose Pre-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Wk 
78 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
D540 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
79 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
80 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
81 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 6 
Protocol - France 
16 September 2016 
 
82 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
Adverse Event 
Mild 
Moderate 
Severe 
Urine 
Proteinuria 
Adults 
1 + proteinuria; 
2+ proteinuria; 
Urinary protein 
g/24 hrs; 
urinary protein < 1.0 g/24 hrs 
urinary protein 1.0 - 3.4 g/24 hrs; 
Children 
-
Urine PIC (Protein/Creatinine) 
Urine P/C >1.9 
ratio 0.5 - 1.9 
Gross hematuria; transfusion, 
Asymptomatic; clinical or diagnostic 
IV medications or 
Symptomatic; urinary catheter or hospitalization indicated; 
Hematuria 
observations only; intervention not 
bladder irrigation indicated 
elective endoscopic, radiologic 
indicated 
or operative intervention 
indicated 
tGrading for this parameter is derived from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept 2007 
*Grading for this parameter is derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, Nov 2014 
tModified for consistency with the ADA and Endocrine Society Guidelines (Seaquist ER, Anderson J, Childs B, et al. 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. 
Diabetes Care 2013;36: 1384-95) 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 5 - France – 19 August 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304801-CS? 
Protocol- France 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
Amendment 5 
19 August 2016 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 5- France- 19 August 2016 
Protocol History: 
Original Protocol: 
Protocol Amendment 1: 
Protocol Amendment 2: 
Protocol Amendment 3: 
Protocol Amendment 4: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  
MD, MBA 
28 August 2015 
2 February 2016 
22 April2016 
9 May 2016 
6 June 2016 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 5 - France 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
19 August 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 5 - France 
Date:  
 
19 August 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 19 August 2016, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................20 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................26 
STUDY GLOSSARY ...................................................................................................................27 
1. 
OBJECTIVES .....................................................................................................................29 
2. 
BACKGROUND AND RATIONALE ..............................................................................29 
2.1 
Overview of Disease ......................................................................................................29 
2.2 
Therapeutic Rationale ....................................................................................................30 
2.3 
Volanesorsen ..................................................................................................................31 
2.3.1 
Mechanism of Action .............................................................................................31 
2.3.2 
Chemistry ...............................................................................................................32 
2.3.3 
Preclinical Experience ............................................................................................33 
2.3.4 
Clinical Experience ................................................................................................34 
2.4 
Rationale for Dose and Schedule of Administration .....................................................35 
3. 
EXPERIMENTAL PLAN ..................................................................................................36 
3.1 
Study Design ..................................................................................................................36 
3.2 
Number of Study Centers ..............................................................................................36 
3.3 
Number of Patients ........................................................................................................36 
3.4 
Overall Study Duration and Follow-up .........................................................................36 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study): Qualification .....................................................................................36 
3.4.2 
Group 3 Patients (did not participate in an index study): Screening/Qualification 36 
3.4.3 
Treatment ................................................................................................................36 
3.4.4 
Post-Treatment .......................................................................................................36 
3.5 
End-of-Study ..................................................................................................................37 
3.6 
Data and Safety Monitoring Board ................................................................................37 
4. 
PATIENT ENROLLMENT ...............................................................................................37 
4.1 
Screening/Qualification .................................................................................................37 
4.2 
Enrollment .....................................................................................................................37 
5. 
PATIENT ELIGIBILITY ..................................................................................................38 
5.1 
Inclusion Criteria ...........................................................................................................38 
5.2 
Exclusion Criteria ..........................................................................................................39 
6. 
STUDY PROCEDURES ....................................................................................................41 
6.1 
Study Schedule ..............................................................................................................41 
6.1.1 
Qualification (Groups 1 and 2) ...............................................................................41 
6.1.2 
Screening and Qualification (Group 3) ..................................................................41 
6.1.3 
Treatment Period ....................................................................................................42 
6.1.4 
Pharmacokinetic (PK) Subgroup ............................................................................42 


ISIS 304801-CS7 
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19 August 2016 
 
6 
6.1.5 
Post-Treatment Period ............................................................................................43 
6.2 
Additional Study Assessments .......................................................................................43 
6.2.1 
Laboratory Assessments .........................................................................................43 
6.2.2 
Physical Exams and Vital Signs .............................................................................43 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................43 
6.2.2.2 
Lipemia Retinalis .............................................................................................44 
6.2.3 
Echocardiography ...................................................................................................44 
6.2.4 
ECG ........................................................................................................................44 
6.2.5 
MRI ........................................................................................................................44 
6.2.6 
Quality of Life Assessments ...................................................................................44 
6.2.7 
Disease Symptom Diary .........................................................................................44 
6.2.8 
Diet Monitoring ......................................................................................................44 
6.2.9 
Family History ........................................................................................................45 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................45 
6.3.1 
Contraception Requirements ..................................................................................45 
6.3.2 
Other Requirements ................................................................................................46 
7. 
STUDY DRUG ....................................................................................................................46 
7.1 
Volanesorsen Description ..............................................................................................46 
7.2 
Packaging and Labeling .................................................................................................46 
7.3 
Study Drug Accountability ............................................................................................47 
8. 
TREATMENT OF PATIENTS .........................................................................................47 
8.1 
Volanesorsen Administration ........................................................................................47 
8.2 
Other Protocol-Required Drugs .....................................................................................47 
8.3 
Other Protocol-Required Treatment Procedures ............................................................47 
8.4 
Treatment Precautions ...................................................................................................47 
8.5 
Safety Monitoring Rules ................................................................................................47 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................48 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................49 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................49 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................49 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................49 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........50 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................50 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................51 
8.5.9 
Acute Pancreatitis ...................................................................................................52 
8.6 
Stopping Rules ...............................................................................................................52 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................52 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................53 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................53 
8.7 
Adjustment of Dose Frequency .....................................................................................55 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
7 
8.8 
Discontinuation of Study Treatment ..............................................................................56 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................56 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .56 
8.9 
Withdrawal of Patients from the Study ..........................................................................57 
8.10 
Concomitant Therapy and Procedures ...........................................................................57 
8.10.1 
Concomitant Therapy .............................................................................................57 
8.10.2 
Concomitant Procedures .........................................................................................58 
8.11 
Treatment Compliance ...................................................................................................58 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................58 
9.1 
Sponsor Review of Safety Information .........................................................................58 
9.2 
Regulatory Requirements ..............................................................................................58 
9.3 
Definitions .....................................................................................................................59 
9.3.1 
Adverse Event ........................................................................................................59 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................59 
9.3.3 
Serious Adverse Event (SAE) ................................................................................60 
9.4 
Monitoring and Recording Adverse Events ...................................................................60 
9.4.1 
Serious Adverse Events ..........................................................................................60 
9.4.2 
Non-Serious Adverse Events ..................................................................................61 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................61 
9.4.3.1 
Relationship to the Study Drug ........................................................................61 
9.4.3.2 
Severity ............................................................................................................61 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................62 
9.4.3.4 
Treatment Given for Adverse Event ................................................................62 
9.4.3.5 
Outcome of the Adverse Event ........................................................................62 
9.4.4 
Adjudication Committees .......................................................................................63 
9.5 
Procedures for Handling Special Situations ..................................................................63 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................63 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............63 
9.5.3 
Dosing Errors .........................................................................................................64 
9.5.4 
Contraception and Pregnancy .................................................................................64 
10. STATISTICAL CONSIDERATIONS ..............................................................................65 
10.1 
Study Endpoints .............................................................................................................65 
10.1.1 
Efficacy Endpoints .................................................................................................65 
10.1.2 
Safety Endpoints .....................................................................................................65 
10.2 
Sample Size ....................................................................................................................65 
10.3 
Populations .....................................................................................................................66 
10.4 
Definition of Baseline ....................................................................................................66 
10.5 
Interim Analysis .............................................................................................................66 
10.6 
Planned Methods of Analysis ........................................................................................66 
10.6.1 
Demographic and Baseline Characteristics ............................................................67 


ISIS 304801-CS7 
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19 August 2016 
 
8 
10.6.2 
Safety Analysis .......................................................................................................67 
10.6.3 
Efficacy Analysis ...................................................................................................67 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................68 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................68 
10.6.4.2 
Immunogenicity Analysis ................................................................................68 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................69 
11.1 
Informed Consent ..........................................................................................................69 
11.2 
Ethical Conduct of the Study .........................................................................................70 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................70 
11.4 
Patient Confidentiality ...................................................................................................70 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................71 
12.1 
Protocol Amendments ....................................................................................................71 
12.2 
Study Termination .........................................................................................................71 
12.3 
Study Documentation and Storage ................................................................................71 
12.4 
Study Monitoring ...........................................................................................................72 
12.5 
Language ........................................................................................................................72 
12.6 
Compensation for Injury ................................................................................................72 
13. REFERENCES ....................................................................................................................73 
14. APPENDICES .....................................................................................................................75 
Appendix A 
Schedule of Procedures ....................................................................................76 
Appendix B 
List of Laboratory Analytes .............................................................................80 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................82 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......84 
 
TABLE OF TABLES 
Page 
Table 1 Volanesorsen (ISIS 304801) Characteristics ................................................................ 46 
Table 2 Actions in Patients With Low Platelet Count ............................................................... 55 
Table 3 Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence ................................................................................................. 59 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 30 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 32 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 34 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
5 - France 
Amendment Date: 
19 August 2016 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 4 dated 6 June 2016: 
1. To enroll FCS patients in this open-label study who did not participate in the 
ISIS 304801–CS6 or ISIS 304801–CS16 index studies. 
For clarity, the protocol now specifies 3 patient groups, with assignment based on prior 
involvement in index studies of ISIS 304801: 
Group 1:  ISIS 304801-CS6 (index study) rollover FCS patients 
Group 2:  ISIS 304801-CS16 (index study) rollover FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
2. To remove language that indicates that lipoprotein lipase (LPL) activity can be measured 
if needed for study qualification for patients in Groups 2 and 3. 
3. To add language to indicate that a second Study Drug rechallenge will not be allowed 
following a platelet count decrease below 75,000/mm3. 
4. To provide clarifications to the platelet safety monitoring rules in Table 2. 
5. To add language to indicate that patients who discontinue early from Study Drug, or the 
study, should be followed as per the platelet monitoring rules shown in Table 2 for the 
first 6 weeks after discontinuing Study Drug and the next platelet count should be taken 
within at least 6 weeks so that patients are monitored for at least 12 weeks after 
discontinuing Study Drug. 
6. Following guidance provided by the ANSM 
a. Following guidance provided by the ANSM, the complete stop of Study Drug in 
patients whose platelet threshold is below 25,000/mm3 will be changed to below 
50,000/mm3 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
10 
b. To add a criteria for treatment discontinuation:  patient participation to the trial must 
be stopped if a decrease in platelets greater than or equal to 50% between two 
consecutive assessments is observed, irrespective of the platelet level 
c. To add in the footnote to Appendix A that in the event of any platelet count less than 
50,000/mm3 or a rate of decline ≥ 50% between two consecutive assessments, 
irrespective of the platelet level, then dosing of a patient with Study Drug 
(ISIS 304801 or placebo) will be stopped permanently 
d. To add in the Exclusion Criteria patients that already had thrombocytopenia 
e. To add language to exclude patients that meet the Exclusion Criteria of their index 
study 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design.  
The following table provides a summary list of major changes to the protocol: 
Protocol Section 
Description of Change 
Rationale 
Protocol Title pages 
Signature page 
Protocol Synopsis:  
Title, Study Population, 
Rationale for Dose and 
Schedule Selection, 
Study Visit Schedule 
and Procedures, 
Statistical 
Considerations 
5.1  Inclusion Criteria 
“Extension” was removed from the study title. 
To note that 
FCS patients 
who did not 
participate in an 
index study will 
also be enrolled. 
Protocol Synopsis: 
Study Design 
3.1  Study Design 
Was: 
This is a multi-center open-label extension study of ISIS 304801-CS6 
and ISIS 304801-CS16 
 
Is: 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the  
ISIS 304801-CS6 or ISIS 304801-CS16 index studies 
To distinguish 
patients who 
participated in 
an index study 
from those who 
did not. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
11 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis: 
Study Population 
5.1  Inclusion Criteria 
Inclusion Criteria 
Was: 
3. Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and 
Investigator judgement.  Patients who are enrolled in 
ISIS 304801-CS16 must also meet the following criteria in order to 
enter into the Extension Study: 
a. 
History of chylomicronemia as evidenced by documentation 
of lactescent serum (a creamy top layer after 
ultracentrifugation of a fasting blood sample) or 
documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of at least 1 of the 
following: 
• 
Confirmed homozygote, compound heterozygote or 
double heterozygote for known loss-of-function mutations 
in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 study 
 
Is: 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety 
profile, per Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in 
order to enter into the open-label study: 
a. History of chylomicronemia as evidenced by documentation 
of lactescent serum (a creamy top layer after 
ultracentrifugation of a fasting blood sample) or 
documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of the following: 
• 
Confirmed homozygote, compound heterozygote or 
double heterozygote for known loss-of-function mutations 
in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening 
 
for the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this 
 
open-label study 
To define the 
inclusion criteria 
for each Group 
of patients. 
LPL removed to 
avoid the 
production of 
heparin induced 
anti-platelet 
antibodies. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
12 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:  
Study Population 
5.2  Exclusion Criteria 
Exclusion Criteria 
Was: 
1. Have any new condition or worsening of existing condition which 
in the opinion of the Investigator would make the patient 
unsuitable for enrollment, or could interfere with the patient 
participating in or completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of 
the study (Section 6.3) 
 
Is: 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening* 
b. HbA1c ≥ 9.0% at Screening* 
c. 
Recent change in anti-diabetic pharmacotherapy (change in 
dosage or addition of new medication within 12 weeks of 
screening* [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during 
the treatment period of the Study [with the exception of 
± 10 units of insulin] 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial 
chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening* 
4. History within 6 months of screening* of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new 
onset angina), stroke, transient ischemic attack or unstable 
congestive cardiac failure requiring a change in medication or 
major surgery within 3 months of screening* 
5. Any of the following laboratory values at Screening* 
a. Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in 
which case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) 
for protein on urine dipstick.  In the event of a positive 
test eligibility may be confirmed by a quantitative total 
urine protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a 
positive test eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power 
field 
• 
Estimated creatinine clearance calculated according to 
the formula of Cockcroft and Gault < 50 mL/min (MDRD 
or CKD-EPI formulas can be used instead of Cockcroft-
Gault for estimation of GFR in patients with low body 
weight after discussion with Sponsor Medical Monitor) 
To define the 
exclusion 
criteria for each 
Group of 
patients and to 
make the 
eligibility criteria 
for the Group 3 
patients 
consistent with 
those for the 
Group 1 index 
study patients. 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
13 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:  
Study Population 
Continued 
5.2  Exclusion Criteria 
Continued 
Exclusion Criteria 
Is: Continued 
c. 
Cardiac Troponin I > ULN at Screening* 
d. 
LDL-C > 130 mg/dL at Screening* 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient 
unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or 
bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening* 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial 
therapy that will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency 
virus (HIV), hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that has 
been successfully treated 
12. Treatment with another investigational drug, biological agent, or 
device within 1-month of screening*, or 5 half-lives of 
investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or 
fibrates unless on a stable dose for at least 3 months prior to 
screening* and dose and regimen expected to remain 
constant during the treatment period.  Patients taking OTC 
omega-3 fatty acids should make every effort to remain on 
the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks 
prior to screening* 
c. 
Systemic corticosteroids or anabolic steroids within 6 weeks 
prior to screening* unless approved by the Sponsor Medical 
Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and 
clozapine) unless on a stable dose for at least 3 months prior 
to screening* and dose and regimen expected to remain 
stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at 
least 4 weeks prior to screening* and dose and regimen 
expected to remain constant during the treatment period 
f. 
Glybera gene therapy within 2 years prior to screening* 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, 
and apixaban) unless on a stable dose for at least 4 weeks 
prior to screening* and regular clinical monitoring is 
performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose 
for at least 4 months prior to screening* and dose and 
regimen expected to remain constant during the treatment 
period 
i. 
Plasma apheresis within 4 weeks prior to screening* or 
planned during the study 
To define the 
exclusion 
criteria for each 
Group of 
patients and to 
make the 
eligibility criteria 
for the Group 3 
patients 
consistent with 
those for the 
Group 1 index 
study patients. 
Continued 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
14 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:  
Study Population 
Continued 
5.2  Exclusion Criteria 
Continued 
Exclusion Criteria 
Is: Continued 
j. 
Prior exposure to ISIS 304801 
k. 
Any other medication unless stable at least 4 weeks prior to 
screening* (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening* or of 
> 499 mL within 60 days of screening* 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, including new or worsening of existing 
condition, which, in the opinion of the Investigator or the Sponsor 
would make the patient unsuitable for inclusion, or could interfere 
with the patient participating in or completing the study 
*(Group 3) or Qualification (Groups 1 and 2) 
To define the 
exclusion 
criteria for each 
Group of 
patients and to 
make the 
eligibility criteria 
for the Group 3 
patients 
consistent with 
those for the 
Group 1 index 
study patients.  
Protocol Synopsis:  
Study Visit Schedule 
and Procedures 
3.4  Overall Study 
Duration and Follow-up 
Appendix A 
Was: 
The study for an individual patient will generally consist of the following 
periods: 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A.   
o 
A 52-week treatment period during which volanesorsen will 
be administered as a once weekly SC injection 
o 
A 13-week post-treatment evaluation period 
 
Is:  
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up 
to 2 weeks (unless approved by the Sponsor).  Please refer 
to Section 4.1 and Appendix A. 
• 
Group 3 patients (did not participate in an index study):  An 
up to 8-week screening and qualification period, including a 
diet stabilization period of at least 6 weeks (screening and 
diet stabilization period may be reduced, per Sponsor 
approval, if the patient is following a diet for optimal control of 
TGs and disease management prior to screening).  Please 
refer to Section 6.1.2 and Appendix A.  
• 
All patients:  
o 
A 52-week treatment period during which volanesorsen 
will be administered as a once weekly SC injection 
o 
A 13-week post-treatment evaluation period 
To distinguish 
the Screening/ 
Qualification 
period for 
patients who 
participated in 
an index study 
from those who 
did not. 
4.1  
Screening/Qualification 
Group 3 (Screening and Qualification):  At the time of consent, the 
patient will be considered enrolled into the study and will be assigned 
a unique screening number before any study procedures, including 
screening procedures, are performed.  At the time of enrollment, 
patients will be assigned a unique patient identification number.  This 
number will be used to identify the patient throughout the trial and 
must be used on all study documentation related to that patient.  The 
screening number and patient identification number must remain 
constant throughout the entire trial.  In the event the patient is 
re-consented and re-screened the patient must be given a new 
screening number.  Screening numbers and patient identification 
numbers, once assigned, will not be re-used 
To define the 
enrollment 
criteria for 
patients who did 
not participate in 
an index study. 


ISIS 304801-CS7 
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Amendment 5 
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19 August 2016 
 
15 
Protocol Section 
Description of Change 
Rationale 
6.1.2  Screening and 
Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, 
patients must sign and date the informed consent form.  An 8-week 
period, including a diet stabilization period of at least 6 weeks 
(screening and diet stabilization period may be reduced, per Sponsor 
approval, if the patient is following a diet for optimal control of TGs and 
disease management prior to screening) is given to perform the 
screening evaluations.  The qualification assessments will be 
performed at Week -2 to -1, ideally after patient eligibility has been 
determined, and on Study Day 1.  Abnormal screening results may be 
retested for review by the Study Medical Monitor for eligibility purposes 
To define the 
Screening and 
Qualification 
procedures for 
patients who did 
not participate in 
an index study. 
8.6.3  Stopping Rules 
for Platelet Count 
Results 
Was: 
If after the first dosing rechallenge the platelet count again falls below 
75,000/mm3, then dosing of the patient must be held until the platelet 
count again returns to at least 100,000/mm3.  The suitability of the 
patient for continued dosing and the need for any further modification 
to treatment schedule or dose (refer to Section 8.7) will be re-
examined by the Investigator in consultation with the Study Medical 
Monitor based on (at least) the factors mentioned above. 
If after the second rechallenge the platelet count falls below 
75,000/mm3 and is subsequently confirmed (see Section 8.5), dosing 
with volanesorsen will be stopped permanently.  The follow-up 
schedule for any events meeting this stopping criterion will be 
determined by the Investigator in consultation with the Study Medical 
Monitor. 
 
Is: 
If after the first dosing rechallenge the platelet count again falls below 
75,000/mm3, then dosing of the patient with Study Drug will be 
stopped permanently. 
Text was 
removed as a 
second 
Study Drug 
rechallenge will 
not be allowed 
following a 
platelet count 
decrease below 
75,000/mm3. 
8.6.3  Stopping Rules 
for Platelet Count 
Results 
Table 2  Actions in 
Patients with Low 
Platelet Count 
Platelet Count 
on Rx 
Drug Dose 
Monitoring 
Normal range, 
> 140K/mm3 
No action 
Monitor every 
2 weeks 
100K-
140K/mm3 
No action 
Closer observation 
Monitor every  
1-week until 
stable* 
75K-100K/mm3 
Permanently reduce 
dose frequency to 
300mg every 2 weeks 
or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 
1-week 
To provide 
clarification to 
the platelet 
safety 
monitoring rules. 
 
Note:  Changes 
are reflected as 
bold underlined 
text. 
 
 


ISIS 304801-CS7 
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19 August 2016 
 
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Protocol Section 
Description of Change 
Rationale 
8.6.3 Stopping Rules for 
Platelet Count Results 
Table 2  Actions in 
Patients with Low 
Platelet Count 
Continued 
Platelet Count 
on Rx 
Drug Dose 
Monitoring 
50K-75K/mm3 
If occurs while on 
dose of 300 mg every 
2 weeks or 150 mg 
every week then 
permanently 
discontinue Study 
Drug, otherwise dose 
pause. 
Dose pause 
When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor 
Closer observation 
Monitor every 
2-3 days until 
2 successive 
values show 
improvement 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/ 
anticoagulant 
medication 
25K-50K/mm3 
or a rate of 
decline ≥ 50% 
between 
2 consecutive 
assessments, 
irrespective of 
the platelet 
level 
Permanently 
discontinue Study Drug   
Closer observation 
Monitor daily until 
2 successive 
values show 
improvement then 
monitor every 
2 3 days until 
platelet count 
stable 
Discontinue 
antiplatelet 
agents/NSAIDS/an
ticoagulant 
medication while 
platelet count 
< 50K/mm3 if 
possible 
 
To provide 
clarification to 
the platelet 
safety 
monitoring rules 
 
Note:  Changes 
are reflected as 
bold underlined 
text 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
17 
Protocol Section 
Description of Change 
Rationale 
8.6.3 Stopping Rules for 
Platelet Count Results 
Table 2  Actions in 
Patients with Low 
Platelet Count 
Continued 
< 25K/mm3 
Permanently 
discontinue Study Drug 
Closer observation: 
Monitor daily until 
2 successive 
values show 
improvement then 
monitor every 
2-3 days until 
platelet count 
stable 
Steroids 
recommended** 
Consider need for 
hospitalization and 
referral to 
hematologist 
Discontinue 
antiplatelet 
agents/NSAIDS/an
ticoagulant 
medication while 
platelet count 
< 50K/mm3 if 
possible 
* 
At least 3 consecutive values measured weekly that are 
stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration 
of high dose steroids.  Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 
40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note: may require continuation with oral 
steroids after methyl prednisolone) 
To provide 
clarification to 
the platelet 
safety 
monitoring rules 
 
Note:  Changes 
are reflected as 
bold underlined 
text 
8.8.1  Follow-up Visits 
for Early Termination 
from Treatment Period 
Was: 
Any patient who discontinues early from the Treatment Period should 
be strongly encouraged to attend applicable landmark visits at 
Weeks 2, 13, 25, 26, and 51, 52 (calculated based on the time elapsed 
since Day 1) to collect fasting lipid panels and conduct safety 
assessments in accordance with the schedule of procedures in 
Appendix A.  Any patient who discontinues treatment after Week 44 
should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last 
dose of Study Drug, in addition to the applicable landmark visits. 
To provide 
guidance to the 
platelet safety 
monitoring rules 
for patients that 
discontinue 
early from the 
Treatment 
Period. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
18 
Protocol Section 
Description of Change 
Rationale 
8.8.1  Follow-up Visits 
for Early Termination 
from Treatment Period 
Continued 
Is: 
Any patient who discontinues early from the Treatment Period should 
be followed as per the platelet monitoring rules shown in Table 2 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  
Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should 
be taken within at least 6 weeks so that patients are monitored for at 
least 12 weeks after discontinuing Study Drug.  Patients should also 
be strongly encouraged to attend applicable landmark visits at 
Weeks 12, 13, 25, 26, and 50, 52 (calculated based on the time 
elapsed since Day 1) to collect fasting lipid panels and conduct safety 
assessments in accordance with the schedule of procedures in 
Appendix A.  Any patient who discontinues treatment after Week 44 
should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last 
dose of Study Drug, in addition to the applicable landmark visits. 
To provide 
guidance to the 
platelet safety 
monitoring rules 
for patients that 
discontinue 
early from the 
Treatment 
Period. 
8.8.2  Follow-up Visits 
for Early Termination 
from Post-Treatment 
Follow-up Period 
Was: 
The patient who requests to withdraw from the study during the Post-
Treatment Follow-up Period should be encouraged to undergo a final 
follow-up visit (Week 65, see Appendix A) prior to leaving the study. 
 
Is: 
The patient who requests to withdraw from the study during the Post-
Treatment Follow-up Period should be encouraged to follow the 
platelet monitoring rules shown in Table 2 in Section 8.6.3 for the first 
6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as 
determined by the Sponsor medical monitor and > 100,000/mm3), the 
next platelet count should be taken within at least 6 weeks so that 
patients are monitored for at least 12 weeks after discontinuing 
Study Drug.  Patients should also be encouraged to undergo a final 
follow-up visit (Week 65, see Appendix A) prior to leaving the study. 
To provide 
guidance to the 
platelet safety 
monitoring rules 
for patients that 
discontinue 
early from the 
Post-Treatment 
Follow-up 
Period. 
8.6.3 
Stopping Rules for 
Platelet Count Results 
Table 2 
Actions in Patients with 
Low Platelet Count 
Was: 
In the event of any platelet count less than 25,000/mm3, or a platelet 
count less than 75,000/mm3 that occurs while the patient is on dosing 
at 300 mg every 2 weeks or 150 mg every week, then dosing of a 
patient with volanesorsen will be stopped permanently. 
 
Is: 
In the event of any platelet count less than 50,000/mm3, or a rate of 
decline ≥ 50% between two consecutive assessments, irrespective of 
the platelet level, then dosing of a patient with volanesorsen will be 
stopped permanently. 
To follow 
guidance 
provided by the 
ANSM to 
provide 
additional 
patient safety 
regarding 
platelet stopping 
rules. 
Appendix A 
Added to Footnote “b”: 
In the event of any platelet count less than 50,000/mm3 or a rate of 
decline ≥ 50% between two consecutive assessments, irrespective of 
the platelet level, then dosing of a patient with Study Drug 
(ISIS 304801 or placebo) will be stopped permanently. 
To follow 
guidance 
provided by the 
ANSM to clarify 
the additional 
patient safety 
regarding 
platelet stopping 
rules in 
Appendix A. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
19 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis: 
Study Population 
5.2 
Exclusion Criteria  
Exclusion Criteria 
Was: 
7. History of bleeding diathesis or coagulopathy or clinically-
significant abnormality in coagulation parameters at Screening 
 
Is: 
7. 
History of thrombocytopenia (platelet count < 100,000/mm3) or 
bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
To exclude 
patients with a 
history of 
thrombocytopeni
a because it 
sometimes 
seems to be 
associated with 
patients 
suffering from 
hyperchylomicro
nemia  
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
20 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will enter a 13-week 
post-treatment evaluation period. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order 
to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for 
the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label 
study  
4. 
Able and willing to participate in a 65-week study 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
21 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening* 
b. HbA1c ≥ 9.0% at Screening* 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage 
or addition of new medication within 12 weeks of screening* [with the 
exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to screening* 
4. History within 6 months of screening* of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of screening* 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
22 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria Continued 
5. Any of the following laboratory values at Screening* 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Screening* 
d. 
LDL-C > 130 mg/dL at Screening* 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding 
diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Screening* 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully 
treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1-month of screening*, or 5 half-lives of investigational agent, 
whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
23 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria Continued 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to screening* and dose 
and regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
screening* 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
screening* unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to screening* and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to screening* and dose and regimen expected to remain 
constant during the treatment period 
f. Glybera gene therapy within 2 years prior to screening* 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening* and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening* and dose and regimen expected to 
remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to screening* or planned 
during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to 
screening* (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening* or of 
> 499 mL within 60 days of screening* 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, including new or worsening of existing 
condition, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the 
patient participating in or completing the study 
*(Group 3) or Qualification (Groups 1 and 2) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
24 
PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up to 
2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A 
• 
Group 3 patients (did not participate in an index study):  An up to 
8-week screening and qualification period, including a diet 
stabilization period of at least 6 weeks (screening and diet 
stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease 
management prior to screening).  Please refer to Section 6.1.2 and 
Appendix A 
• 
All patients: 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
A 13-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter the 13-week post-treatment 
evaluation period. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
25 
PROTOCOL SYNOPSIS Continued 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
26 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
SCREENING PERIOD 
Weeks -8 to -2 (Group 3 patients only) 
QUALIFICATION 
PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD assessments 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
27 
STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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STUDY GLOSSARY Continued 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or  
ISIS 304801-CS16 index studies 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification 
A period of up to 2 weeks (unless approved by the Sponsor) is given to complete qualification 
assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and Appendix A. 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification 
An up to 8-week screening and qualification period, including a diet stabilization period of at 
least 6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if 
the patient is following a diet for optimal control of TGs and disease management prior to 
screening.  Please refer to Section 6.1.2 and Appendix A. 
3.4.3 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.4 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 2 Study Center visits on 
Weeks 58 and 65. 


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3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Screening/Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open-label study are performed.   
Groups 1 and 2 (Qualification):  During the qualification period, the eligibility of the patient to 
enroll in the open-label study will be determined.  Final assessments from the ISIS 304801-CS6 
or ISIS 304801-CS16 studies may be used for qualification.  A period of up to 2 weeks after 
completion of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the 
Sponsor) is given to complete qualification.  Qualified patients will retain the unique patient 
identification number that was assigned to them during the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies.  The patient identification number will be used to identify the 
patient throughout the extension trial and must be used on all study documentation related to that 
patient.  The patient identification number must remain constant throughout the extension trial. 
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered 
enrolled into the study and will be assigned a unique screening number before any study 
procedures, including screening procedures, are performed.  At the time of enrollment, patients 
will be assigned a unique patient identification number.  This number will be used to identify the 
patient throughout the trial and must be used on all study documentation related to that patient.  
The screening number and patient identification number must remain constant throughout the 
entire trial.  In the event the patient is re-consented and re-screened the patient must be given a 
new screening number.  Screening numbers and patient identification numbers, once assigned, 
will not be re-used. 
4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all Screening (Group3) and 
qualification assessments have been completed and after the Investigator has verified that they 
are eligible per criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to 
enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 


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5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order to enter into the 
open-label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
c. Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the  
 
ISIS 304801-CS16 index study 
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label study 
4. Able and willing to participate in a 65-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 


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to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria  
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening* 
b. HbA1c ≥ 9.0% at Screening* 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of screening* [with the exception of ± 10 units of 
insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening* 
4. History within 6 months of screening* of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack 
or unstable congestive cardiac failure requiring a change in medication or major surgery 
within 3 months of screening* 
5. Any of the following laboratory values at Screening* 
a. Hepatic: 
• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• ALT > 2.0 x ULN 
• AST > 2.0 x ULN 
b. Renal: 
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick.  In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs 


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• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick.  In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field 
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Screening* 
d. LDL-C > 130 mg/dL at Screening* 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of thrombocytopenia (platelet count < 100,000/mm3) or bleeding diathesis or 
coagulopathy or clinically-significant abnormality in coagulation parameters at 
Screening* 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
12. Treatment with another investigational drug, biological agent, or device within 1-month 
of screening*, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable 
dose for at least 3 months prior to screening* and dose and regimen expected to 
remain constant during the treatment period.  Patients taking OTC omega-3 fatty 
acids should make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening* 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening* 
unless approved by the Sponsor Medical Monitor 


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d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to screening* and dose and regimen expected to 
remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
screening* and dose and regimen expected to remain constant during the treatment 
period 
f. Glybera gene therapy within 2 years prior to screening* 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to screening* and regular clinical monitoring is 
performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to screening* and dose and regimen expected to remain constant during the treatment 
period 
i. Plasma apheresis within 4 weeks prior to screening* or planned during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening* (Occasional 
or intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening* or of > 499 mL within 
60 days of screening* 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or 
placebo) 
17. Have any other conditions, including new or worsening of existing condition, which, in 
the opinion of the Investigator or the Sponsor would make the patient unsuitable for 
inclusion, or could interfere with the patient participating in or completing the study 
*(Group 3) or Qualification (Groups 1 and 2) 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification (Groups 1 and 2) 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  An 8-week period, including a diet stabilization period of at least 


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6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease management prior to screening) 
is given to perform the screening evaluations.  The qualification assessments will be performed 
at Week -2 to -1, ideally after patient eligibility has been determined, and on Study Day 1.  
Abnormal screening results may be retested for review by the Study Medical Monitor for 
eligibility purposes 
6.1.3 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 2.5, 
4, 6, 8, 10, 12, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 40, 42, 44, 46, 48, and 50 may be 
conducted by a home healthcare nurse.  Approval for study procedures to be conducted by a 
home healthcare nurse on other outpatient visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples and samples drawn locally should also 
be sent to the central laboratory for analysis whenever possible.  Every effort should be made to 
ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  Dosing 
instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.4 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 


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withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.5 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the 13-week 
post-treatment evaluation period.  This period consists of 4 Study Center visits on Weeks 54, 56, 
and 58 (which may be conducted by a home healthcare nurse), and Week 65 as outlined in the 
Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and determined not to have met a stopping rule before dosing 
can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to ensure that the count 
has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 


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6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 rollover patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 


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6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent* or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 


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*Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 


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7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 


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In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 


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1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 2 in Section 8.6.3. 
Additional lab tests will be determined by the Sponsor Medical Monitor or designee in 
consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 


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to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 


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The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1-week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 


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If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
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8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 2 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 50,000/mm3, or a rate of decline ≥ 50% between two 
consecutive assessments, irrespective of the platelet level, then dosing of a patient with 
volanesorsen will be stopped permanently.  Platelet count will be monitored daily until 
2 successive values show improvement then monitored every 2-3 days until platelet count is 
stable. 
Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone). 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks or a reduced dose of 150 mg per week (refer to Section 8.7).  The suitability of the 
patient for continued dosing will be determined by the Investigator in consultation with the Study 
Medical Monitor and will be based on factors such as the original rate of decline in the patient’s 
platelet count, whether any bleeding events were experienced by the patient, and the speed of 
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If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Following a rechallenge platelet count should be tested every week until count is stable. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
 


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Table 2 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every 1-week until stable* 
75K-100K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 1-week 
50K-75K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 or a rate of 
decline ≥ 50% between 
two consecutive 
assessments, irrespective of 
the platelet level 
Permanently discontinue Study Drug   
Closer observation 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
< 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended** 
Consider need for hospitalization 
and referral to hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
At least 3 consecutive values measured weekly that are stable as determined by the Sponsor Medical Monitor 
and > 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methyl prednisolone) 
 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 2 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 


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schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in Table 2 in Section 8.6.3 for the first 6 weeks after 
discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3), the next platelet count should be taken within at least 6 weeks so that patients 
are monitored for at least 12 weeks after discontinuing Study Drug.  Patients should also be 
strongly encouraged to attend applicable landmark visits at Weeks 12, 13, 25, 26, and 50, 52 
(calculated based on the time elapsed since Day 1) to collect fasting lipid panels and conduct 
safety assessments in accordance with the Schedule of Procedures in Appendix A.  Any patient 
who discontinues treatment after Week 44 should also be strongly encouraged to attend a final 
follow-up visit (Week 65 visit assessments) approximately 13 weeks after their last dose of 
Study Drug, in addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 2 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 
6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  


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Patients should also be encouraged to undergo a final follow-up visit (Week 65, see Appendix A) 
prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 


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Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 


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Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 3 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 


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A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 


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follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 


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• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 


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• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
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• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 


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10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 evaluable PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline for safety will be the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 
will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 
All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 


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10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
studies.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index studies. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index studies, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index studies. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index studies. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index studies. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index studies.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index studies for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 


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The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group of the index studies. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification for Group 1 and 2 patients by their 
prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 2 
patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the index 
study (and all patients in Group 3) will receive the first treatment of volanesorsen (single-dose 
PK), while patients who received volanesorsen in the index studies had been on volanesorsen 
treatment for 12 months (ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data 
collected from these patients reflect steady-state PK.  The maximum observed drug 
concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  Area under the plasma concentration-time curve from time zero to 
24 hours (AUC0-24hr) will be calculated using the linear trapezoidal rule.  Apparent systemic 
(plasma) clearance after SC administration (CL0-24hr /F0-24hr) will be calculated from  
CL0-24hr /F0-24hr = Actual Dose/AUC0-24hr.  Mean residence time (MRT) from time zero to 
24 hours after the SC administration will be calculated from the equation,  
MRT0-24hr = AUMC0-24hr /AUC0-24hr, where AUMC0-24hr is the area under the moment plasma 
concentration-time curve from time zero to 24 hours after the SC administration.  Other PK 
parameters, as appropriate, may be determined or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 


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listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the duration of ADA 
response (number of days between Tfirst and Tlast) if appropriate, the last ADA sample collection 
day, and subject - peak titer if applicable, will be listed by their prior treatment in Study 
ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16.  Furthermore, onset, duration, and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
 
 


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11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 


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No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 


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13. 
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and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
75 
 
 
 
 
 
 
 
14. 
APPENDICES 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
76 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 5
Protocol - France 
19 August 2016
 
77 
Appendix A Schedule of Procedures 
Study Period 
Screen/ 
Run In
a 
Qual
a 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-8 to -2 
-2 to -
1 
Wk
1 
Wk 
2.5
Wk
4 
Wk
6 
Wk
8 
Wk 
10
Month 3 
Wk 
15
&
17 
Wk 
19 
Wk 
21
&
23 
Month 6 
Wk 
28
& 
30 
Wk
32 
Wk 
34
&
36 
Wk
38 
Wk 
40 
& 
42 
Wk
44 
Wk 
46 
& 
48 
Month 12 
Wk 
54
&
56 
Wk 
58
Wk 
65 
Wk
12 
Wk
13 
Wk 
25 
Wk
26 
Wk 
50 
Wk 52
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2
11
22
36 
50 
64
78 
85 
99
&
113
127
141
&
155
169 176
190
& 
204 
218
232
&
246
260
274
&
288
302
316
& 
330
344
358 
372
&
386
400 449 
Visit Window+/- Days 
0 
0 
0 
0
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X
j
X
j
X
j 
X
j 
X
j 
X
j
X
j
X 
X
j 
X
j 
X
j 
X
j 
X 
X
j 
X
j 
X
j 
X 
X
j 
X
j 
X
j 
X
j 
X 
X
j 
X
j 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Physical Examination 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
k 
 
 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
k 
 
 
 
 
 
 
 
 
X
k 
 
 
 
Blood Draw (Fasting)
c 
Chemistry Panel 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC with Differential
b 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
X 
 
 
X 
 
X 
 
X
X 
 
 
 
X
 
X 
 
 
 
X 
 
 
 
X
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
X
n 
X
n 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Sedimentation Rate 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - Volanesorsen 
 
 
X
l 
X
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
FSH (women only, if applicable) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test
d 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Archived Serum & Plasma 
Samples
e 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Troponin I
o 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
78 
Appendix A Schedule of Procedures Continued 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-8 to -2 
-2 to -
1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Urinalysisc 
X 
X 
Xm 
 
 
X 
 
X 
 
 
Xm 
 
Xm 
 
 
Xm 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
 
Xm 
Xm 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
Genetic testing for FCS 
diagnosis (if not available in 
medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC 
Injection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
Assessment(s) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Food/Drink Diary (quarterly)h 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Diet/Alcohol Counselingi 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Screening (Group 3) and Qualification procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1-week and determined not to have met a stopping rule before dosing can continue.  If there is no reportable platelet count within 14 days of the last 
platelet count, the Investigator will contact the patient to hold dosing until a new platelet count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that 
the patient could be approaching the dose pause rule of 75,000/mm3.  In the event of any platelet count less than 50,000/mm3 or a rate of decline ≥ 50% 
between two consecutive assessments, irrespective of the platelet level, then dosing of a patient with Study Drug (ISIS 304801 or placebo) will be stopped 
permanently.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 5
Protocol - France 
19 August 2016
 
79 
Appendix A Schedule of Procedures Continued 
Legend Text Continued 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 [ISIS 304801-CS16 rollover patients] and 
Group 3) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
g 
Genetic testing can be conducted for study qualification (Group 2 [ISIS 304801-CS16 rollover patients] and Group 3); genetic testing will only be conducted if 
allowed in the geographic region and only after the patient has given specific written informed consent for genetic testing 
h 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
j 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
k 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
l 
Full or abbreviated PK profile (see Appendix C) 
m 
Expanded urinalysis (see Appendix B) 
n 
HbA1c only 
o 
All abnormal troponin samples will be rerun at the central laboratory and also analyzed for CK-MB 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
80 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
81 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
82 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
83 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
84 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
85 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
86 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol - France 
19 August 2016 
 
87 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
Adverse Event 
Mild 
Moderate 
Severe 
Urine 
Proteinuria 
Adults 
1 + proteinuria; 
2+ proteinuria; 
Urinary protein 
g/24 hrs; 
urinary protein < 1.0 g/24 hrs 
urinary protein 1.0 - 3.4 g/24 hrs; 
Children 
-
Urine PIC (Protein/Creatinine) 
Urine P/C >1.9 
ratio 0.5 - 1.9 
Gross hematuria; transfusion, 
Asymptomatic; clinical or diagnostic 
IV medications or 
Symptomatic; urinary catheter or hospitalization indicated; 
Hematuria 
observations only; intervention not 
bladder irrigation indicated 
elective endoscopic, radiologic 
indicated 
or operative intervention 
indicated 
tGrading for this parameter is derived from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept 2007 
*Grading for this parameter is derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, Nov 2014 
tModified for consistency with the ADA and Endocrine Society Guidelines (Seaquist ER, Anderson J, Childs B, et al. 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. 
Diabetes Care 2013;36: 1384-95) 


 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator:
Akcea Therapeutics
55 Cambridge Parkway, Suite 100
Cambridge, MA 02142
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 5 – 6 July 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 5
Protocol 
 
6 July 2016
 
2 
 
 
ISIS 304801-CS7 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 5 – 6 July 2016 
 
 
Protocol History: 
Original Protocol: 
 
28 August 2015 
Protocol Amendment 1: 
2 February 2016 
Protocol Amendment 2: 
22 April 2016 
Protocol Amendment 3: 
9 May 2016 
Protocol Amendment 4: 
6 June 2016 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
______________________ 
MD, MBA 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 5 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open-Label Study 
Volanesorsen (ISIS 304801) 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone:
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
6 July 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Amendment: 
Amendment 5 
Date:  
 
6 July 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Study of Volanesorsen Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)”, dated 6 July 2016, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................18 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................24 
STUDY GLOSSARY ...................................................................................................................25 
1. 
OBJECTIVES .....................................................................................................................27 
2. 
BACKGROUND AND RATIONALE ..............................................................................27 
2.1 
Overview of Disease ......................................................................................................27 
2.2 
Therapeutic Rationale ....................................................................................................28 
2.3 
Volanesorsen ..................................................................................................................29 
2.3.1 
Mechanism of Action .............................................................................................29 
2.3.2 
Chemistry ...............................................................................................................30 
2.3.3 
Preclinical Experience ............................................................................................31 
2.3.4 
Clinical Experience ................................................................................................32 
2.4 
Rationale for Dose and Schedule of Administration .....................................................33 
3. 
EXPERIMENTAL PLAN ..................................................................................................34 
3.1 
Study Design ..................................................................................................................34 
3.2 
Number of Study Centers ..............................................................................................34 
3.3 
Number of Patients ........................................................................................................34 
3.4 
Overall Study Duration and Follow-up .........................................................................34 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification ....................................................................................34 
3.4.2 
Group 3 Ppgatients (did not participate in an index study):  
Screening/Qualification ..........................................................................................34 
3.4.3 
Treatment ................................................................................................................34 
3.4.4 
Post-Treatment .......................................................................................................34 
3.5 
End-of-Study ..................................................................................................................35 
3.6 
Data and Safety Monitoring Board ................................................................................35 
4. 
PATIENT ENROLLMENT ...............................................................................................35 
4.1 
Screening/Qualification .................................................................................................35 
4.2 
Enrollment .....................................................................................................................35 
5. 
PATIENT ELIGIBILITY ..................................................................................................36 
5.1 
Inclusion Criteria ...........................................................................................................36 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-CS16) 
Index Study Roll-over Patients ......................................................................................37 
6. 
STUDY PROCEDURES ....................................................................................................40 
6.1 
Study Schedule ..............................................................................................................40 
6.1.1 
Qualification (Groups 1 and 2) ...............................................................................40 
6.1.2 
Screening and Qualification (Group 3) ..................................................................40 


ISIS 304801-CS7 
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Protocol 
6 July 2016 
 
6 
6.1.3 
Treatment Period ....................................................................................................40 
6.1.4 
Pharmacokinetic (PK) Subgroup ............................................................................41 
6.1.5 
Post-Treatment Period ............................................................................................41 
6.2 
Additional Study Assessments .......................................................................................41 
6.2.1 
Laboratory Assessments .........................................................................................41 
6.2.2 
Physical Exams and Vital Signs .............................................................................41 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................42 
6.2.2.2 
Lipemia Retinalis .............................................................................................42 
6.2.3 
Echocardiography ...................................................................................................42 
6.2.4 
ECG ........................................................................................................................42 
6.2.5 
MRI ........................................................................................................................42 
6.2.6 
Quality of Life Assessments ...................................................................................42 
6.2.7 
Disease Symptom Diary .........................................................................................42 
6.2.8 
Diet Monitoring ......................................................................................................43 
6.2.9 
Family History ........................................................................................................43 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................43 
6.3.1 
Contraception Requirements ..................................................................................43 
6.3.2 
Other Requirements ................................................................................................44 
7. 
STUDY DRUG ....................................................................................................................44 
7.1 
Volanesorsen Description ..............................................................................................44 
7.2 
Packaging and Labeling .................................................................................................45 
7.3 
Study Drug Accountability ............................................................................................45 
8. 
TREATMENT OF PATIENTS .........................................................................................45 
8.1 
Volanesorsen Administration ........................................................................................45 
8.2 
Other Protocol-Required Drugs .....................................................................................45 
8.3 
Other Protocol-Required Treatment Procedures ............................................................46 
8.4 
Treatment Precautions ...................................................................................................46 
8.5 
Safety Monitoring Rules ................................................................................................46 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................46 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................47 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................47 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................48 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................48 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........48 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................48 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................49 
8.5.9 
Acute Pancreatitis ...................................................................................................50 
8.6 
Stopping Rules ...............................................................................................................50 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................50 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................51 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
7 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................51 
8.7 
Adjustment of Dose Frequency .....................................................................................53 
8.8 
Discontinuation of Study Treatment ..............................................................................54 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................54 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .54 
8.9 
Withdrawal of Patients from the Study ..........................................................................55 
8.10 
Concomitant Therapy and Procedures ...........................................................................55 
8.10.1 
Concomitant Therapy .............................................................................................55 
8.10.2 
Concomitant Procedures .........................................................................................56 
8.11 
Treatment Compliance ...................................................................................................56 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................56 
9.1 
Sponsor Review of Safety Information .........................................................................56 
9.2 
Regulatory Requirements ..............................................................................................56 
9.3 
Definitions .....................................................................................................................57 
9.3.1 
Adverse Event ........................................................................................................57 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................57 
9.3.3 
Serious Adverse Event (SAE) ................................................................................58 
9.4 
Monitoring and Recording Adverse Events ...................................................................58 
9.4.1 
Serious Adverse Events ..........................................................................................58 
9.4.2 
Non-Serious Adverse Events ..................................................................................59 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................59 
9.4.3.1 
Relationship to the Study Drug ........................................................................59 
9.4.3.2 
Severity ............................................................................................................59 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................60 
9.4.3.4 
Treatment Given for Adverse Event ................................................................60 
9.4.3.5 
Outcome of the Adverse Event ........................................................................60 
9.4.4 
Adjudication Committees .......................................................................................61 
9.5 
Procedures for Handling Special Situations ..................................................................61 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................61 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............61 
9.5.3 
Dosing Errors .........................................................................................................62 
9.5.4 
Contraception and Pregnancy .................................................................................62 
10. STATISTICAL CONSIDERATIONS ..............................................................................63 
10.1 
Study Endpoints .............................................................................................................63 
10.1.1 
Efficacy Endpoints .................................................................................................63 
10.1.2 
Safety Endpoints .....................................................................................................63 
10.2 
Sample Size ....................................................................................................................63 
10.3 
Populations .....................................................................................................................64 
10.4 
Definition of Baseline ....................................................................................................64 
10.5 
Interim Analysis .............................................................................................................64 


ISIS 304801-CS7 
CONFIDENTIAL 
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Protocol 
6 July 2016 
 
8 
10.6 
Planned Methods of Analysis ........................................................................................64 
10.6.1 
Demographic and Baseline Characteristics ............................................................65 
10.6.2 
Safety Analysis .......................................................................................................65 
10.6.3 
Efficacy Analysis ...................................................................................................65 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................66 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................66 
10.6.4.2 
Immunogenicity Analysis ................................................................................66 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................67 
11.1 
Informed Consent ..........................................................................................................67 
11.2 
Ethical Conduct of the Study .........................................................................................67 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................68 
11.4 
Patient Confidentiality ...................................................................................................68 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................68 
12.1 
Protocol Amendments ....................................................................................................68 
12.2 
Study Termination .........................................................................................................69 
12.3 
Study Documentation and Storage ................................................................................69 
12.4 
Study Monitoring ...........................................................................................................70 
12.5 
Language ........................................................................................................................70 
12.6 
Compensation for Injury ................................................................................................70 
13. REFERENCES ....................................................................................................................71 
14. APPENDICES .....................................................................................................................73 
Appendix A 
Schedule of Procedures ....................................................................................74 
Appendix B 
List of Laboratory Analytes .............................................................................78 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................80 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities ......82 
 
TABLE OF TABLES 
Page 
Table 1 Volanesorsen (ISIS 304801) Characteristics ................................................................ 45 
Table 2 Actions in Patients With Low Platelet Count ............................................................... 53 
Table 3 Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence ................................................................................................. 57 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 28 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 30 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 32 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 5
Protocol 
 
6 July 2016
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
5 
Amendment Date: 
6 July 2016 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 4 dated 6 June 2016: 
1. To enroll FCS patients in this open label study who did not participate in the 
ISIS 304801–CS6 or ISIS 304801–CS16 index studies. 
For clarity, the protocol now specifies 3 patient groups, with assignment based on prior 
involvement in index studies of ISIS 304801: 
Group 1:  ISIS 304801-CS6 (index study) rollover FCS patients 
Group 2:  ISIS 304801-CS16 (index study) rollover FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
2. To remove language that indicates that lipoprotein lipase (LPL) activity can be measured 
if needed for study qualification for patients in Groups 2 and 3. 
3. To add language to indicate that a second Study Drug rechallenge will not be allowed 
following a platelet count decrease below 75,000/mm3. 
4. To provide clarifications to the platelet safety monitoring rules in Table 2. 
5. To add language to indicate that patients who discontinue early from Study Drug, or the 
study, should be followed as per the platelet monitoring rules shown in Table 2 for the 
first 6 weeks after discontinuing Study Drug and the next platelet count should be taken 
within at least 6 weeks so that patients are monitored for at least 12 weeks after 
discontinuing Study Drug. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design.  
The following table provides a summary list of major changes to the protocol: 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
10 
Protocol Section 
Description of Change 
Rationale 
Protocol Title pages 
Signature page 
Protocol Synopsis:  
Title, Study Population, 
Rationale for Dose and 
Schedule Selection, 
Study Visit Schedule 
and Procedures, 
Statistical 
Considerations 
5.1  Inclusion Criteria 
“Extension” was removed from the study title 
To note that 
FCS patients 
who did not 
participate in an 
index study will 
also be enrolled 
Protocol Synopsis: 
Study Design 
3.1  Study Design 
Was: 
This is a multi-center open-label extension study of ISIS 304801-CS6 
and ISIS 304801-CS16 
 
Is: 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the  
ISIS 304801-CS6 or ISIS 304801-CS16 index studies 
To distinguish 
patients who 
participated in 
an index study 
from those who 
did not 
Protocol Synopsis: 
Study Population 
5.1  Inclusion Criteria 
Was: 
3. Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and 
Investigator judgement.  Patients who are enrolled in 
ISIS 304801-CS16 must also meet the following criteria in order to 
enter into the Extension Study: 
a. History of chylomicronemia as evidenced by documentation 
of lactescent serum (a creamy top layer after 
ultracentrifugation of a fasting blood sample) or 
documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of at least 1 of the 
following: 
• 
Confirmed homozygote, compound heterozygote or 
double heterozygote for known loss-of-function mutations 
in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 study 
To define the 
inclusion criteria 
for each Group 
of patients 
LPL removed to 
avoid the 
production of 
heparin induced 
anti-platelet 
antibodies 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
11 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis: 
Study Population 
Continued 
5.1  Inclusion Criteria 
Continued 
Is: Continued 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety 
profile, per Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in 
order to enter into the open-label study: 
a. History of chylomicronemia as evidenced by documentation 
of lactescent serum (a creamy top layer after 
ultracentrifugation of a fasting blood sample) or 
documentation of fasting TG measurement ≥ 880 mg/dL 
(10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of the following: 
• 
Confirmed homozygote, compound heterozygote or 
double heterozygote for known loss-of-function mutations 
in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening 
for the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this 
open-label study 
To define the 
inclusion criteria 
for each Group 
of patients 
LPL removed to 
avoid the 
production of 
heparin induced 
anti-platelet 
antibodies 
Continued 
Protocol Synopsis:  
Study Population 
5.2  Exclusion Criteria 
Was: 
Exclusion Criteria 
1. Have any new condition or worsening of existing condition which 
in the opinion of the Investigator would make the patient 
unsuitable for enrollment, or could interfere with the patient 
participating in or completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of 
the study (Section 6.3) 
 
Is: 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 
(ISIS 304801-CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which 
in the opinion of the Investigator would make the patient 
unsuitable for enrollment, or could interfere with the patient 
participating in or completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of 
the study (Section 6.3) 
 
Exclusion Criteria for Group 3 (patients who did not participate in 
an index study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. 
Recent change in anti-diabetic pharmacotherapy (change in 
dosage or addition of new medication within 12 weeks of 
screening [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during 
the treatment period of the Study [with the exception of 
± 10 units of insulin] 
e. Current use of GLP-1 agonists 
To define the 
exclusion 
criteria for each 
Group of 
patients and to 
make the 
eligibility criteria 
for the Group 3 
patients 
consistent with 
those for the 
Group 1 index 
study patients  
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
12 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:  
Study Population 
Continued 
5.2  Exclusion Criteria 
Continued 
Is: Continued 
Exclusion Criteria for Group 3 (patients who did not participate in 
an index study) 
2. Severe hypertriglyceridemia other than due to familial 
chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening 
4. History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new 
onset angina), stroke, transient ischemic attack or unstable 
congestive cardiac failure requiring a change in medication or 
major surgery within 3 months of screening 
5. Any of the following laboratory values at Screening 
a. Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in 
which case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) 
for protein on urine dipstick.  In the event of a positive 
test eligibility may be confirmed by a quantitative total 
urine protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a 
positive test eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power 
field 
• 
Estimated creatinine clearance calculated according to 
the formula of Cockcroft and Gault < 50 mL/min (MDRD 
or CKD-EPI formulas can be used instead of Cockcroft-
Gault for estimation of GFR in patients with low body 
weight after discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Screening 
d. 
LDL-C > 130 mg/dL at Screening 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient 
unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-
significant abnormality in coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial 
therapy that will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency 
virus (HIV), hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that has 
been successfully treated 
12. Treatment with another investigational drug, biological agent, or 
device within 1-month of screening, or 5 half-lives of 
investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
To define the 
exclusion 
criteria for each 
Group of 
patients and to 
make the 
eligibility criteria 
for the Group 3 
patients 
consistent with 
those for the 
Group 1 index 
study patients 
Continued 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
13 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:  
Study Population 
Continued 
5.2  Exclusion Criteria 
Continued 
Is: Continued 
Exclusion Criteria for Group 3 (patients who did not participate in 
an index study) Continued 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or 
fibrates unless on a stable dose for at least 3 months prior to 
screening and dose and regimen expected to remain 
constant during the treatment period.  Patients taking OTC 
omega-3 fatty acids should make every effort to remain on 
the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks 
prior to screening 
c. 
Systemic corticosteroids or anabolic steroids within 6 weeks 
prior to screening unless approved by the Sponsor Medical 
Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and 
clozapine) unless on a stable dose for at least 3 months prior 
to screening and dose and regimen expected to remain 
stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at 
least 4 weeks prior to screening and dose and regimen 
expected to remain constant during the treatment period 
f. 
Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, 
and apixaban) unless on a stable dose for at least 4 weeks 
prior to screening and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose 
for at least 4 months prior to screening and dose and regimen 
expected to remain constant during the treatment period 
i. 
Plasma apheresis within 4 weeks prior to screening or 
planned during the study 
j. 
Prior exposure to ISIS 304801 
k. 
Any other medication unless stable at least 4 weeks prior to 
screening (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of 
> 499 mL within 60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, which, in the opinion of the 
Investigator or the Sponsor would make the patient unsuitable for 
inclusion, or could interfere with the patient participating in or 
completing the study 
To define the 
exclusion 
criteria for each 
Group of 
patients and to 
make the 
eligibility criteria 
for the Group 3 
patients 
consistent with 
those for the 
Group 1 index 
study patients 
Continued 
Protocol Synopsis:  
Study Visit Schedule 
and Procedures 
3.4  Overall Study 
Duration and Follow-up 
Appendix A 
Was: 
The study for an individual patient will generally consist of the following 
periods: 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A.   
o 
A 52-week treatment period during which volanesorsen will 
be administered as a once weekly SC injection 
o 
A 13-week post-treatment evaluation period 
To distinguish 
the Screening/ 
Qualification 
period for 
patients who 
participated in 
an index study 
from those who 
did not 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
14 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis:  
Study Visit Schedule 
and Procedures 
Continued 
3.4  Overall Study 
Duration and Follow-up 
Continued 
Appendix A Continued 
Is: Continued 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up 
to 2 weeks (unless approved by the Sponsor).  Please refer 
to Section 4.1 and Appendix A. 
• 
Group 3 patients (did not participate in an index study):  An 
up to 8-week screening and qualification period, including a 
diet stabilization period of at least 6 weeks (screening and 
diet stabilization period may be reduced, per Sponsor 
approval, if the patient is following a diet for optimal control of 
TGs and disease management prior to screening).  Please 
refer to Section 6.1.2 and Appendix A.  
• 
All patients:  
o 
A 52-week treatment period during which volanesorsen 
will be administered as a once weekly SC injection 
o 
A 13-week post-treatment evaluation period 
To distinguish 
the Screening/ 
Qualification 
period for 
patients who 
participated in 
an index study 
from those who 
did not 
Continued 
4.1  Screening / 
Qualification 
Group 3 (Screening and Qualification):  At the time of consent, the 
patient will be considered enrolled into the study and will be assigned 
a unique screening number before any study procedures, including 
screening procedures, are performed.  At the time of enrollment, 
patients will be assigned a unique patient identification number.  This 
number will be used to identify the patient throughout the trial and 
must be used on all study documentation related to that patient.  The 
screening number and patient identification number must remain 
constant throughout the entire trial.  In the event the patient is 
re-consented and re-screened the patient must be given a new 
screening number.  Screening numbers and patient identification 
numbers, once assigned, will not be re-used 
To define the 
enrollment 
criteria for 
patients who did 
not participate in 
an index study 
6.1.2  Screening and 
Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, 
patients must sign and date the informed consent form.  An 8-week 
period, including a diet stabilization period of at least 6 weeks 
(screening and diet stabilization period may be reduced, per Sponsor 
approval, if the patient is following a diet for optimal control of TGs and 
disease management prior to screening) is given to perform the 
screening evaluations.  The qualification assessments will be 
performed at Week -2 to -1, ideally after patient eligibility has been 
determined, and on Study Day 1.  Abnormal screening results may be 
retested for review by the Study Medical Monitor for eligibility purposes 
To define the 
Screening and 
Qualification 
procedures for 
patients who did 
not participate in 
an index study 
8.6.3  Stopping Rules 
for Platelet Count 
Results 
Was: 
If after the first dosing rechallenge the platelet count again falls below 
75,000/mm3, then dosing of the patient must be held until the platelet 
count again returns to at least 100,000/mm3.  The suitability of the 
patient for continued dosing and the need for any further modification 
to treatment schedule or dose (refer to Section 8.7) will be re-
examined by the Investigator in consultation with the Study Medical 
Monitor based on (at least) the factors mentioned above. 
If after the second rechallenge the platelet count falls below 
75,000/mm3 and is subsequently confirmed (see Section 8.5), dosing 
with volanesorsen will be stopped permanently.  The follow-up 
schedule for any events meeting this stopping criterion will be 
determined by the Investigator in consultation with the Study Medical 
Monitor. 
Text was 
removed as a 
second 
Study Drug 
rechallenge will 
not be allowed 
following a 
platelet count 
decrease below 
75,000/mm3 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 5
Protocol 
 
6 July 2016
 
15 
Protocol Section 
Description of Change 
Rationale 
8.6.3  Stopping Rules 
for Platelet Count 
Results Continued 
Is: 
If after the first dosing rechallenge the platelet count again falls below 
75,000/mm3, then dosing of the patient with Study Drug will be 
stopped permanently. 
Text was 
removed as a 
second 
Study Drug 
rechallenge will 
not be allowed 
following a 
platelet count 
decrease below 
75,000/mm3  
8.6.3  Stopping Rules 
for Platelet Count 
Results 
Table 2  Actions in 
Patients with Low 
Platelet Count 
Platelet Count 
on Rx 
Drug Dose 
Monitoring 
Normal range, 
> 140K/mm3 
No action 
Monitor every 
2 weeks 
100K-
140K/mm3 
No action 
Closer observation 
Monitor every  
1-week until 
stable* 
75K-100K/mm3 
Permanently reduce 
dose frequency to 
300mg every 2 weeks 
or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 
1-week 
50K-75K/mm3 
If occurs while on 
dose of 300 mg every 
2 weeks or 150 mg 
every week then 
permanently 
discontinue Study 
Drug, otherwise dose 
pause. 
Dose pause 
When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor 
Closer observation 
Monitor every 
2-3 days until 
2 successive 
values show 
improvement 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/ 
anticoagulant 
medication 
 
To provide 
clarification to 
the platelet 
safety 
monitoring rules 
 
Note:  Changes 
are reflected as 
bold underlined 
text 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 5
Protocol 
 
6 July 2016
 
16 
Protocol Section 
Description of Change 
Rationale 
8.6.3 Stopping Rules for 
Platelet Count Results 
Table 2  Actions in 
Patients with Low 
Platelet Count 
Continued 
Platelet Count 
on Rx 
Drug Dose 
Monitoring 
25K-50K/mm3 
If occurs while on dose 
of 300 mg every 
2 weeks or 150 mg 
every week then 
permanently 
discontinue Study 
Drug, otherwise dose 
pause. 
When platelet count 
returns to > 100K/mm3 
restart dosing at dose 
frequency of 300 mg 
every 2 weeks or 
150 mg weekly only if 
approved by Sponsor 
Medical Monitor  
Closer observation 
Monitor daily until 
2 successive 
values show 
improvement then 
monitor every 
2 3 days until 
platelet count 
stable 
Discontinue 
antiplatelet 
agents/NSAIDS/an
ticoagulant 
medication while 
platelet count 
< 50K/mm3 if 
possible 
< 25K/mm3 
Permanently 
discontinue Study Drug 
Closer observation: 
Monitor daily until 
2 successive 
values show 
improvement then 
monitor every 
2-3 days until 
platelet count 
stable 
Steroids 
recommended** 
Consider need for 
hospitalization and 
referral to 
hematologist 
Discontinue 
antiplatelet 
agents/NSAIDS/an
ticoagulant 
medication while 
platelet count 
< 50K/mm3 if 
possible 
* 
At least 3 consecutive values measured weekly that are 
stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration 
of high dose steroids.  Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 
1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; 
or Methylprednisolone 30 mg/kg/day for 7 days (note: may require 
continuation with oral steroids after methyl prednisolone) 
To provide 
clarification to 
the platelet 
safety 
monitoring rules 
 
Note:  Changes 
are reflected as 
bold underlined 
text 
Continued 
 
 


ISIS 304801-CS7 
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17 
Protocol Section 
Description of Change 
Rationale 
8.8.1  Follow-up Visits 
for Early Termination 
from Treatment Period 
Was: 
Any patient who discontinues early from the Treatment Period should 
be strongly encouraged to attend applicable landmark visits at 
Weeks 2, 13, 25, 26, and 51, 52 (calculated based on the time elapsed 
since Day 1) to collect fasting lipid panels and conduct safety 
assessments in accordance with the schedule of procedures in 
Appendix A.  Any patient who discontinues treatment after Week 44 
should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last 
dose of Study Drug, in addition to the applicable landmark visits. 
 
Is: 
Any patient who discontinues early from the Treatment Period should 
be followed as per the platelet monitoring rules shown in Table 2 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  
Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should 
be taken within at least 6 weeks so that patients are monitored for at 
least 12 weeks after discontinuing Study Drug.  Patients should also 
be strongly encouraged to attend applicable landmark visits at 
Weeks 12, 13, 25, 26, and 50, 52 (calculated based on the time 
elapsed since Day 1) to collect fasting lipid panels and conduct safety 
assessments in accordance with the schedule of procedures in 
Appendix A.  Any patient who discontinues treatment after Week 44 
should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last 
dose of Study Drug, in addition to the applicable landmark visits. 
To provide 
guidance to the 
platelet safety 
monitoring rules 
for patients that 
discontinue 
early from the 
Treatment 
Period 
8.8.2  Follow-up Visits 
for Early Termination 
from Post-Treatment 
Follow-up Period 
Was: 
The patient who requests to withdraw from the study during the Post-
Treatment Follow-up Period should be encouraged to undergo a final 
follow-up visit (Week 65, see Appendix A) prior to leaving the study. 
 
Is: 
The patient who requests to withdraw from the study during the Post-
Treatment Follow-up Period should be encouraged to follow the 
platelet monitoring rules shown in Table 2 in Section 8.6.3 for the first 
6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as 
determined by the Sponsor medical monitor and > 100,000/mm3), the 
next platelet count should be taken within at least 6 weeks so that 
patients are monitored for at least 12 weeks after discontinuing 
Study Drug.  Patients should also be encouraged to undergo a final 
follow-up visit (Week 65, see Appendix A) prior to leaving the study. 
To provide 
guidance to the 
platelet safety 
monitoring rules 
for patients that 
discontinue 
early from the 
Post-Treatment 
Follow-up 
Period 
 
 


ISIS 304801-CS7 
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PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with 
volanesorsen (volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies 
All patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will enter a 13-week 
post-treatment evaluation period. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or 
ISIS 304801-CS16 (index studies) with an acceptable safety profile, per 
Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order 
to enter into the open-label study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of the following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
c. 
Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for 
the ISIS 304801-CS16 index study  
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label 
study  
4. 
Able and willing to participate in a 65-week study 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-
CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the 
opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage 
or addition of new medication within 12 weeks of screening [with the 
exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the 
treatment period of the Study (with the exception of ± 10 units of 
insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia 
syndrome 
3. Active pancreatitis within 4 weeks prior to screening 
 
 


ISIS 304801-CS7 
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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) Continued 
4. History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina), stroke, transient ischemic attack or unstable congestive cardiac 
failure requiring a change in medication or major surgery within 3 months 
of screening 
5. Any of the following laboratory values at Screening 
a. 
Hepatic: 
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 
• 
ALT > 2.0 x ULN 
• 
AST > 2.0 x ULN 
b. 
Renal: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick.  In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs 
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick.  In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field 
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 50 mL/min (MDRD or  
CKD-EPI formulas can be used instead of Cockcroft-Gault 
for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. 
Cardiac Troponin I > ULN at Screening 
d. 
LDL-C > 130 mg/dL at Screening 
e. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable for 
inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix that has been successfully 
treated 
12. Treatment with another investigational drug, biological agent, or device 
within 1-month of screening, or 5 half-lives of investigational agent, 
whichever is longer 


ISIS 304801-CS7 
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Amendment 5 
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21 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Exclusion Criteria for Group 3 (patients who did not participate in an index 
study) Continued 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless 
on a stable dose for at least 3 months prior to screening and dose and 
regimen expected to remain constant during the treatment period.  
Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to 
screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to 
screening unless approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) 
unless on a stable dose for at least 3 months prior to screening and 
dose and regimen expected to remain stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to screening and dose and regimen expected to remain 
constant during the treatment period 
f. Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening and regular clinical monitoring is performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening and dose and regimen expected to 
remain constant during the treatment period 
i. Plasma apheresis within 4 weeks prior to screening or planned during 
the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening 
(Occasional or intermittent use of over-the-counter medications will be 
allowed at Investigator’s discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of 
> 499 mL within 60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug 
(ISIS 304801 or placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or the 
Sponsor would make the patient unsuitable for inclusion, or could 
interfere with the patient participating in or completing the study 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
 
 


ISIS 304801-CS7 
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22 
PROTOCOL SYNOPSIS Continued 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6 and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies (Section 2.4) which included a subset of patients with 
FCS.  The same dose of 300 mg once weekly will be used in this open-label 
study of FCS patients.  
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
Group 1 and 2 patients (participated in ISIS 304801-CS6 or 
ISIS 304801-CS16 index study):  A qualification period of up to 
2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A 
• 
Group 3 patients (did not participate in an index study):  An up to 
8-week screening and qualification period, including a diet 
stabilization period of at least 6 weeks (screening and diet 
stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease 
management prior to screening).  Please refer to Section 6.1.2 and 
Appendix A 
• 
All patients: 
o 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
o 
A 13-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the open-label study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter the 13-week post-treatment 
evaluation period. 
 
 


ISIS 304801-CS7 
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6 July 2016 
 
23 
PROTOCOL SYNOPSIS Continued 
Safety and Tolerability Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an open-label study. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


ISIS 304801-CS7 
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24 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
SCREENING PERIOD 
Weeks -8 to -2 (Group 3 patients only) 
QUALIFICATION 
PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD assessments 


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25 
STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


ISIS 304801-CS7 
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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of dosing and extended dosing 
with volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an 
open-label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label study of: 
Group 1:  ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2:  ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3:  FCS patients who did not participate in the ISIS 304801-CS6 or  
ISIS 304801-CS16 index studies 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
3.4.1 
Group 1 and 2 Patients (participated in ISIS 304801-CS6 or ISIS 304801–CS16 
index study):  Qualification 
A period of up to 2 weeks (unless approved by the Sponsor) is given to complete qualification 
assessments outlined in the Schedule of Procedures.  Please refer to Section 4.1 and Appendix A. 
3.4.2 
Group 3 Patients (did not participate in an index study):  Screening/Qualification 
An up to 8-week screening and qualification period, including a diet stabilization period of at 
least 6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if 
the patient is following a diet for optimal control of TGs and disease management prior to 
screening.  Please refer to Section 6.1.2 and Appendix A. 
3.4.3 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule of Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.4 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 2 Study Center visits on 
Weeks 58 and 65. 


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3.5 
End-of-Study 
The End-of-Study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Screening/Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open-label study are performed.   
Groups 1 and 2 (Qualification):  During the qualification period, the eligibility of the patient to 
enroll in the open-label study will be determined.  Final assessments from the ISIS 304801-CS6 
or ISIS 304801-CS16 studies may be used for qualification.  A period of up to 2 weeks after 
completion of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the 
Sponsor) is given to complete qualification.  Qualified patients will retain the unique patient 
identification number that was assigned to them during the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies.  The patient identification number will be used to identify the 
patient throughout the extension trial and must be used on all study documentation related to that 
patient.  The patient identification number must remain constant throughout the extension trial. 
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered 
enrolled into the study and will be assigned a unique screening number before any study 
procedures, including screening procedures, are performed.  At the time of enrollment, patients 
will be assigned a unique patient identification number.  This number will be used to identify the 
patient throughout the trial and must be used on all study documentation related to that patient.  
The screening number and patient identification number must remain constant throughout the 
entire trial.  In the event the patient is re-consented and re-screened the patient must be given a 
new screening number.  Screening numbers and patient identification numbers, once assigned, 
will not be re-used. 
4.2 
Enrollment 
Patients will be enrolled into the treatment phase of the study after all Screening (Group3) and 
qualification assessments have been completed and after the Investigator has verified that they 
are eligible per criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to 
enrollment. 


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Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Groups 1 and 2:  Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and Investigator judgement. 
 
Groups 2 and 3:  Patients must also meet the following criteria in order to enter into the 
open-label Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
c. Group 2:  Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the  
 
ISIS 304801-CS16 index study 
Group 3:  Fasting TG ≥ 750 mg/dL at Screening for this open-label study 
4. Able and willing to participate in a 65-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 


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b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria for Group 1 (ISIS 304801-CS6) and Group 2 (ISIS 304801-
CS16) Index Study Roll-over Patients 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 
Exclusion Criteria for Group 3 (patients who did not participate in an index study) 
1. Diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of screening [with the exception of ± 10 units of insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units of insulin) 
e. Current use of GLP-1 agonists 
2. Severe hypertriglyceridemia other than due to familial chylomicronemia syndrome 
3. Active pancreatitis within 4 weeks prior to screening 
4. History within 6 months of screening of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina), stroke, transient ischemic attack 
or unstable congestive cardiac failure requiring a change in medication or major surgery 
within 3 months of screening 


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5. Any of the following laboratory values at Screening 
a. Hepatic: 
• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be  
≤ 3 mg/dL 
• ALT > 2.0 x ULN 
• AST > 2.0 x ULN 
b. Renal: 
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick.  In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs 
• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick.  In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field 
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 50 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
c. Cardiac Troponin I > ULN at Screening 
d. LDL-C > 130 mg/dL at Screening 
e. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Screening 
8. History of heart failure with NYHA greater than Class II 
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 


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12. Treatment with another investigational drug, biological agent, or device within 1-month 
of screening, or 5 half-lives of investigational agent, whichever is longer 
13. Unwilling to comply with lifestyle requirements (Section 6.3) 
14. Use of any of the following: 
a. Statins, omega-3 fatty acids (prescription and OTC), or fibrates unless on a stable 
dose for at least 3 months prior to screening and dose and regimen expected to remain 
constant during the treatment period.  Patients taking OTC omega-3 fatty acids should 
make every effort to remain on the same brand throughout the study 
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening 
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening unless 
approved by the Sponsor Medical Monitor 
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to screening and dose and regimen expected to remain 
stable throughout the study 
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
screening and dose and regimen expected to remain constant during the treatment 
period 
f. Glybera gene therapy within 2 years prior to screening 
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to screening and regular clinical monitoring is 
performed 
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to screening and dose and regimen expected to remain constant during the treatment 
period 
i. Plasma apheresis within 4 weeks prior to screening or planned during the study 
j. Prior exposure to ISIS 304801 
k. Any other medication unless stable at least 4 weeks prior to screening (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
15. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 
60 days of screening 
16. Known hypersensitivity to any of the excipients of the Study Drug (ISIS 304801 or 
placebo) 
17. Have any other conditions, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the patient participating 
in or completing the study 


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6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification (Groups 1 and 2) 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Screening and Qualification (Group 3) 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  An 8-week period, including a diet stabilization period of at least 
6 weeks (screening and diet stabilization period may be reduced, per Sponsor approval, if the 
patient is following a diet for optimal control of TGs and disease management prior to screening) 
is given to perform the screening evaluations.  The qualification assessments will be performed 
at Week -2 to -1, ideally after patient eligibility has been determined, and on Study Day 1.  
Abnormal screening results may be retested for review by the Study Medical Monitor for 
eligibility purposes 
6.1.3 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the open-label study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 2.5, 
4, 6, 8, 10, 12, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 40, 42, 44, 46, 48, and 50 may be 
conducted by a home healthcare nurse.  Approval for study procedures to be conducted by a 
home healthcare nurse on other outpatient visit days will require prior approval by the Sponsor.  
Patients must be fasted prior to drawing all blood samples and samples drawn locally should also 
be sent to the central laboratory for analysis whenever possible.  Every effort should be made to 
ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  Dosing 
instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 


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6.1.4 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.5 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the 13-week 
post-treatment evaluation period.  This period consists of 4 Study Center visits on Weeks 54, 56, 
and 58 (which may be conducted by a home healthcare nurse), and Week 65 as outlined in the 
Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and determined not to have met a stopping rule before dosing 
can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to ensure that the count 
has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 


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always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 rollover patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 


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6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent* or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 


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effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
*Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 


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Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or ISIS 304801-CS16), will receive a reduced dose or 
dose frequency of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 
and 8.6.  Patients entering this CS7 study having dose or dose frequency reduced in the CS16 
index study after 13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can 
receive the 300 mg once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 


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8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 


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In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 2 in Section 8.6.3. 
Additional lab tests will be determined by the Sponsor Medical Monitor or designee in 
consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 


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8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 


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≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1-week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 


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In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 


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1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 2 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 25,000/mm3, or a platelet count less than 75,000/mm3 
that occurs while the patient is on dosing at 300 mg every 2 weeks or 150 mg every week then 
dosing of a patient with volanesorsen will be stopped permanently.  Platelet count will be 
monitored daily until 2 successive values show improvement then monitored every 2-3 days until 
platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 


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0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone). 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered 
to> 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg 
every 2 weeks or a reduced dose of 150 mg per week (refer to Section 8.7).  The suitability of the 
patient for continued dosing will be determined by the Investigator in consultation with the Study 
Medical Monitor and will be based on factors such as the original rate of decline in the patient’s 
platelet count, whether any bleeding events were experienced by the patient, and the speed of 
recovery of platelet count upon holding of dosing. 
If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient with Study Drug will be stopped permanently. 
Following a rechallenge platelet count should be tested every week until count is stable. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 


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Table 2 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every 1-week until stable* 
75K-100K/mm3 
Permanently reduce dose frequency to 
300 mg every 2 weeks or reduce dose to 
150 mg weekly 
Closer observation 
Monitor every 1-week 
50K-75K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor  
Closer observation 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
< 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended** 
Consider need for hospitalization 
and referral to hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
At least 3 consecutive values measured weekly that are stable as determined by the Sponsor Medical Monitor 
and > 100,000/mm3 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methyl prednisolone) 
 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 2 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 


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schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in Table 2 in Section 8.6.3 for the first 6 weeks after 
discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and 
> 100,000/mm3), the next platelet count should be taken within at least 6 weeks so that patients 
are monitored for at least 12 weeks after discontinuing Study Drug.  Patients should also be 
strongly encouraged to attend applicable landmark visits at Weeks 12, 13, 25, 26, and 50, 52 
(calculated based on the time elapsed since Day 1) to collect fasting lipid panels and conduct 
safety assessments in accordance with the Schedule of Procedures in Appendix A.  Any patient 
who discontinues treatment after Week 44 should also be strongly encouraged to attend a final 
follow-up visit (Week 65 visit assessments) approximately 13 weeks after their last dose of 
Study Drug, in addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to follow the platelet monitoring rules shown in Table 2 in 
Section 8.6.3 for the first 6 weeks after discontinuing Study Drug.  Following this period, if the 
platelet count is stable (at least 3 consecutive values that are stable as determined by the Sponsor 
Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at least 
6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug.  


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Patients should also be encouraged to undergo a final follow-up visit (Week 65, see Appendix A) 
prior to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 


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Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 


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Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 3 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 


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A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 


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follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen, e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 


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• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 


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9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
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9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are 
defined as the average of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints 
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an open-label study. 


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10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 evaluable PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient in Groups 1 and 2:  
Group 1 (ISIS 304801-CS6) or Group 2 (ISIS 304801-CS16) index study baseline and the 
baseline in this open-label study, which is defined as the average of Day 1 pre-dose assessment 
and the last measurement prior to Day 1 (e.g., qualification assessments or assessments from 
final visit of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline for safety will be the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this open-label study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 
will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 
All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 


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10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
studies.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index studies. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index studies, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index studies. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index studies. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index studies. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index studies.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index studies for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 


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The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group of the index studies. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification for Group 1 and 2 patients by their 
prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open-label study from 
the intensive PK subgroup, following a single-dose (i.e., single-dose PK) or multiple doses (i.e., 
steady-state PK), depending on their earlier treatment in the index studies (Group 1 and 2 
patients).  On Week 1 Day 1 of the open-label study, patients who received placebo in the index 
study (and all patients in Group 3) will receive the first treatment of volanesorsen (single-dose 
PK), while patients who received volanesorsen in the index studies had been on volanesorsen 
treatment for 12 months (ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data 
collected from these patients reflect steady-state PK.  The maximum observed drug 
concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  Area under the plasma concentration-time curve from time zero to 
24 hours (AUC0-24hr) will be calculated using the linear trapezoidal rule.  Apparent systemic 
(plasma) clearance after SC administration (CL0-24hr /F0-24hr) will be calculated from  
CL0-24hr /F0-24hr = Actual Dose/AUC0-24hr.  Mean residence time (MRT) from time zero to 
24 hours after the SC administration will be calculated from the equation,  
MRT0-24hr = AUMC0-24hr /AUC0-24hr, where AUMC0-24hr is the area under the moment plasma 
concentration-time curve from time zero to 24 hours after the SC administration.  Other PK 
parameters, as appropriate, may be determined or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 


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listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 (Groups 1 and 2) 
and study day.  Subject ADA status (positive/negative or not evaluable) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the duration of ADA 
response (number of days between Tfirst and Tlast) if appropriate, the last ADA sample collection 
day, and subject - peak titer if applicable, will be listed by their prior treatment in Study 
ISIS 304801-CS6 and ISIS 304801-CS16 (Groups 1 and 2) and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16.  Furthermore, onset, duration, and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 


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11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 


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12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
 
 


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12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 


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13. 
REFERENCES 
Altmann KH, Fabbrot D, Dean NM, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia. N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


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14. 
APPENDICES 
 
 
 


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Appendix A 
Schedule of Procedures 
 
 


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Appendix A Schedule of Procedures 
Study Period 
Screen/ 
Run Ina 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-8 to -2 
-2 to -
1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
Xj 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Physical Examination 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MRI (liver/spleen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
Xk 
 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC with Differentialb 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
X 
PG 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Sedimentation Rate 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complement (C5a, Bb) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - Volanesorsen 
 
 
Xl 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Anti-Volanesorsen Antibodies 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
FSH (women only, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Archived Serum & Plasma 
Samplese 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 


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Appendix A Schedule of Procedures Continued 
Study Period 
Screen/ 
Run In
a 
Qual
a 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-8 to -2 
-2 to -
1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-56 to -
15 
-14 to 
-7 
1 
2 11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Urinalysis
c 
X 
X 
X
m 
 
 
X 
 
X 
 
 
X
m 
 
X
m 
 
 
X
m 
 
X
m 
 
X
m 
 
X
m 
 
 
X
m 
 
X
m 
X
m 
Fundus Photography
f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
k 
 
 
 
Genetic testing for FCS 
diagnosis (if not available in 
medical history)
g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC 
Injection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Symptom Diary (weekly) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
Assessment(s) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Food/Drink Diary (quarterly)
h 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Diet/Alcohol Counseling
i 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
Adverse Events
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Screening and Qualification (Group 3) procedures performed (Please refer to Sections 3.4, 4.1, and 6.1.2) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1-week and determined not to have met a stopping rule before dosing can continue.  If there is no reportable platelet count within 14 days of the last 
platelet count, the Investigator will contact the patient to hold dosing until a new platelet count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that 
the patient could be approaching the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
77 
Appendix A Schedule of Procedures Continued 
Legend Text Continued 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (Group 2 [ISIS 304801-CS16 rollover patients] and 
Group 3) and repeated at Week 52 (Please refer to Section 6.2.2.2) 
g 
Genetic testing can be conducted for study qualification (Group 2 [ISIS 304801-CS16 rollover patients] and Group 3); genetic testing will only be conducted if 
allowed in the geographic region and only after the patient has given specific written informed consent for genetic testing 
h 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
i 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
j 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
k 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
l 
Full or abbreviated PK profile (see Appendix C) 
m 
Expanded urinalysis (see Appendix B) 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
78 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
79 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
80 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
81 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
82 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
83 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
84 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 5 
Protocol 
6 July 2016 
 
85 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
Adverse Event 
Mild 
Moderate 
Severe 
Urine 
Proteinuria 
Adults 
1 + proteinuria; 
2+ proteinuria; 
Urinary protein 
g/24 hrs; 
urinary protein < 1.0 g/24 hrs 
urinary protein 1.0 - 3.4 g/24 hrs; 
Children 
-
Urine PIC (Protein/Creatinine) 
Urine P/C >1.9 
ratio 0.5 - 1.9 
Gross hematuria; transfusion, 
Asymptomatic; clinical or diagnostic 
IV medications or 
Symptomatic; urinary catheter or hospitalization indicated; 
Hematuria 
observations only; intervention not 
bladder irrigation indicated 
elective endoscopic, radiologic 
indicated 
or operative intervention 
indicated 
tGrading for this parameter is derived from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept 2007 
*Grading for this parameter is derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, Nov 2014 
tModified for consistency with the ADA and Endocrine Society Guidelines (Seaquist ER, Anderson J, Childs B, et al. 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. 
Diabetes Care 2013;36: 1384-95) 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 4 –6 June 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
2 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 4 – 6 June 2016 
 
Protocol History: 
Original Protocol: 
 
28 August 2015 
Protocol Amendment 1: 
2 February 2016 
Protocol Amendment 2: 
22 April 2016 
Protocol Amendment 3: 
9 May 2016 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
__________________________________ 
 M.D., M.B.A. 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 4 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
6 June 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome 
(FCS) 
Amendment: 
Amendment 4 
Date:  
 
6 June 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Extension Study of Volanesorsen Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS)”, dated 6 June 2016, and agree to conduct the study 
as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................13 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................16 
STUDY GLOSSARY ...................................................................................................................17 
1. 
OBJECTIVES .....................................................................................................................19 
2. 
BACKGROUND AND RATIONALE ..............................................................................19 
2.1 
Overview of Disease ......................................................................................................19 
2.2 
Therapeutic Rationale ....................................................................................................20 
2.3 
Volanesorsen ..................................................................................................................21 
2.3.1 
Mechanism of Action .............................................................................................21 
2.3.2 
Chemistry ...............................................................................................................22 
2.3.3 
Preclinical Experience ............................................................................................23 
2.3.4 
Clinical Experience ................................................................................................24 
2.4 
Rationale for Dose and Schedule of Administration .....................................................25 
3. 
EXPERIMENTAL PLAN ..................................................................................................26 
3.1 
Study Design ..................................................................................................................26 
3.2 
Number of Study Centers ..............................................................................................26 
3.3 
Number of Patients ........................................................................................................26 
3.4 
Overall Study Duration and Follow-up .........................................................................26 
3.4.1 
Qualification ...........................................................................................................26 
3.4.2 
Treatment ................................................................................................................26 
3.4.3 
Post-Treatment .......................................................................................................26 
3.5 
End of Study ..................................................................................................................26 
3.6 
Data and Safety Monitoring Board ................................................................................27 
4. 
PATIENT ENROLLMENT ...............................................................................................27 
4.1 
Qualification ..................................................................................................................27 
4.2 
Enrollment .....................................................................................................................27 
5. 
PATIENT ELIGIBILITY ..................................................................................................27 
5.1 
Inclusion Criteria ...........................................................................................................27 
5.2 
Exclusion Criteria ..........................................................................................................28 
6. 
STUDY PROCEDURES ....................................................................................................29 
6.1 
Study Schedule ..............................................................................................................29 
6.1.1 
Qualification ...........................................................................................................29 
6.1.2 
Treatment Period ....................................................................................................29 
6.1.3 
Pharmacokinetic (PK) Subgroup ............................................................................29 
6.1.4 
Post-Treatment Period ............................................................................................30 
6.2 
Additional Study Assessments .......................................................................................30 
6.2.1 
Laboratory Assessments .........................................................................................30 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
6 
6.2.2 
Physical Exams and Vital Signs .............................................................................30 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................30 
6.2.2.2 
Lipemia Retinalis .............................................................................................31 
6.2.3 
Echocardiography ...................................................................................................31 
6.2.4 
ECG ........................................................................................................................31 
6.2.5 
MRI ........................................................................................................................31 
6.2.6 
Quality of Life Assessments ...................................................................................31 
6.2.7 
Disease Symptom Diary .........................................................................................31 
6.2.8 
Diet Monitoring ......................................................................................................31 
6.2.9 
Family History ........................................................................................................32 
6.2.10 
Lipoprotein Lipase Activity Sample Collection .....................................................32 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................32 
6.3.1 
Contraception Requirements ..................................................................................32 
6.3.2 
Other Requirements ................................................................................................33 
7. 
STUDY DRUG ....................................................................................................................33 
7.1 
Volanesorsen Description ..............................................................................................33 
7.2 
Packaging and Labeling .................................................................................................34 
7.3 
Study Drug Accountability ............................................................................................34 
8. 
TREATMENT OF PATIENTS .........................................................................................34 
8.1 
Volanesorsen Administration ........................................................................................34 
8.2 
Other Protocol-Required Drugs .....................................................................................34 
8.3 
Other Protocol-Required Treatment Procedures ............................................................34 
8.4 
Treatment Precautions ...................................................................................................34 
8.5 
Safety Monitoring Rules ................................................................................................34 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................35 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................36 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................36 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................36 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................37 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........37 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................37 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................38 
8.5.9 
Acute Pancreatitis ...................................................................................................39 
8.6 
Stopping Rules ...............................................................................................................39 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................39 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................40 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................40 
8.7 
Adjustment of Dose Frequency .....................................................................................42 
8.8 
Discontinuation of Study Treatment ..............................................................................43 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................43 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
7 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .43 
8.9 
Withdrawal of Patients from the Study ..........................................................................43 
8.10 
Concomitant Therapy and Procedures ...........................................................................44 
8.10.1 
Concomitant Therapy .............................................................................................44 
8.10.2 
Concomitant Procedures .........................................................................................45 
8.11 
Treatment Compliance ...................................................................................................45 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................45 
9.1 
Sponsor Review of Safety Information .........................................................................45 
9.2 
Regulatory Requirements ..............................................................................................45 
9.3 
Definitions .....................................................................................................................46 
9.3.1 
Adverse Event ........................................................................................................46 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................46 
9.3.3 
Serious Adverse Event (SAE) ................................................................................46 
9.4 
Monitoring and Recording Adverse Events ...................................................................47 
9.4.1 
Serious Adverse Events ..........................................................................................47 
9.4.2 
Non-Serious Adverse Events ..................................................................................47 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................48 
9.4.3.1 
Relationship to the Study Drug ........................................................................48 
9.4.3.2 
Severity ............................................................................................................48 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................48 
9.4.3.4 
Treatment Given for Adverse Event ................................................................49 
9.4.3.5 
Outcome of the Adverse Event ........................................................................49 
9.4.4 
Adjudication Committees .......................................................................................49 
9.5 
Procedures for Handling Special Situations ..................................................................50 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................50 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............50 
9.5.3 
Dosing Errors .........................................................................................................50 
9.5.4 
Contraception and Pregnancy .................................................................................51 
10. STATISTICAL CONSIDERATIONS ..............................................................................51 
10.1 
Study Endpoints .............................................................................................................51 
10.1.1 
Efficacy Endpoints .................................................................................................51 
10.1.2 
Safety Endpoints .....................................................................................................52 
10.2 
Sample Size ....................................................................................................................52 
10.3 
Populations .....................................................................................................................52 
10.4 
Definition of Baseline ....................................................................................................53 
10.5 
Interim Analysis .............................................................................................................53 
10.6 
Planned Methods of Analysis ........................................................................................53 
10.6.1 
Demographic and Baseline Characteristics ............................................................53 
10.6.2 
Safety Analysis .......................................................................................................53 
10.6.3 
Efficacy Analysis ...................................................................................................54 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
8 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................54 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................54 
10.6.4.2 
Immunogenicity Analysis ................................................................................55 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................56 
11.1 
Informed Consent ..........................................................................................................56 
11.2 
Ethical Conduct of the Study .........................................................................................56 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................56 
11.4 
Patient Confidentiality ...................................................................................................57 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................57 
12.1 
Protocol Amendments ....................................................................................................57 
12.2 
Study Termination .........................................................................................................57 
12.3 
Study Documentation and Storage ................................................................................57 
12.4 
Study Monitoring ...........................................................................................................58 
12.5 
Language ........................................................................................................................59 
12.6 
Compensation for Injury ................................................................................................59 
13. REFERENCES ....................................................................................................................60 
14. APPENDICES .....................................................................................................................62 
Appendix A 
Schedule of Procedures ....................................................................................63 
Appendix B 
List of Laboratory Analytes .............................................................................67 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................69 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......71 
 
 
TABLE OF TABLES 
Page 
Table 1 Volanesorsen (ISIS 304801) Characteristics ................................................................ 33 
Table 2 Actions in Patients With Low Platelet Count ............................................................... 42 
Table 3 Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence ................................................................................................. 46 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 20 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 22 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 24 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
4 
Amendment Date: 
6 June 2016 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 3 dated 9 May 2016: 
1. To add hematology blood draws so that platelet counts are measured every 2 weeks 
during the treatment period and every 2 weeks for the first 6 weeks after the last dose of 
Study Drug. 
2. To update the platelet safety monitoring rules (shown in Table 2).   
3. To add language to indicate that if there is no reportable platelet count within 14 days of 
the last platelet count, the Investigator will contact the patient to hold dosing until a new 
platelet count is obtained and reviewed.  
4. To add language to indicate that all platelet count results will be promptly reviewed by 
the Investigator to ensure that the count has not met the stopping rule and to determine 
whether the rate of decline is suggestive that the patient could be approaching the dose 
pause rule of 75,000/mm3. 
5. To change the platelet dose pause/stopping rule from 50,000/mm3 to 75,000/mm3 and to 
add that when platelet count returns to ≥ 100,000/mm3 dosing may be continued but at a 
reduced dose frequency of 300 mg every 2 weeks or a reduced dose of 150 mg per week 
and only if approved by the Sponsor Medical Monitor. 
6. To add language to indicate that in the event of any platelet count less than 25,000/mm3, 
or a platelet count less than 50,000/mm3 that occurs while the patient is on dosing at 
300 mg every 2 weeks or 150 mg per week, then dosing of a patient with volanesorsen 
will be stopped permanently.  Platelet count will be monitored daily until 2 successive 
values show improvement then monitored every 2-3 days until platelet count is stable. 
7. To add language to indicate that administration of steroids is recommended for patients 
whose platelet count is less than 25,000/mm3 and to provide treatment guidelines for the 
administration of steroids.   
8. To add a Table summarizing actions to be taken in the event of a low platelet count. 


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9. To add language to indicate that patients will receive a suitable dose or dose frequency of 
volanesorsen, when they enter this CS7 study, based on safety/tolerability or non-
safety/tolerability dosing rules. 
Minor administrative changes or corrections (not included in the list of changes) have been made 
throughout the protocol in order to improve the overall clarity of the protocol but these changes 
do not impact the study design. 
The following table provides a summary list of changes to the protocol: 
Protocol Section 
Description of Change 
Rationale 
Section 6.1.2 
Treatment Period 
Section 6.1.4 Post-
Treatment Period 
Appendix A 
Schedule of 
Procedures 
Hematology blood draws added to Weeks 2.5, 6, 10, 15, 17, 21, 23, 28, 
30, 34, 36, 40, 42, 46, 48, 50, 54, 56 and removed from Weeks 16, 22, 
29, 35, 41, 47 and 51. 
To implement 
more frequent 
evaluation of 
platelet counts to 
assess platelet 
fluctuations 
during the course 
of the study and 
to increase 
platelet count 
monitoring for 
safety purposes 
Section 8.5.2 
Safety Monitoring 
for Platelet Count 
Results 
Actions to be taken in the event of reduced platelet count are shown in 
Table 2 in Section 8.6.3.   
To increase 
platelet count 
monitoring for 
safety purposes 
Section 6.2.1 
Laboratory 
Assessments 
Section 8.6.3 
Stopping Rules for 
Platelet Count 
Results  
Appendix A 
Schedule of 
Procedures 
If there is no reportable platelet count within 14 days of the last platelet 
count, the Investigator will contact the patient to hold dosing until a new 
platelet count is obtained and reviewed. 
To increase 
platelet count 
monitoring and 
provide added 
patient safety 
regarding 
ISIS 304801 
dose exposure 
Section 6.2.1 
Laboratory 
Assessments 
Appendix A 
Schedule of 
Procedures 
All platelet count results will be promptly reviewed by the Investigator to 
ensure that the count has not met the stopping rule and to determine 
whether the rate of decline is suggestive that the patient could be 
approaching the dose pause rule of 75,000/mm3.   
To increase 
platelet count 
monitoring for 
safety purposes 
Section 8.6.3 
Stopping Rules for 
Platelet Count 
Results  
Dose pause/ stopping rule changed from 50,000/mm3 to 75,000/mm3 and 
when platelet count returns to ≥ 100,000/mm3 dosing may be continued 
but at a reduced dose frequency of 300 mg every 2 weeks or a reduced 
dose of 150 mg per week and only if approved by the Sponsor Medical 
Monitor. 
To increase 
platelet count 
monitoring and 
provide added 
patient safety 
regarding 
ISIS 304801 
dose exposure 
 
 


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Protocol Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping Rules for 
Platelet Count 
Results 
In the event of any platelet count less than 25,000/mm3, or a platelet 
count less than 50,000/mm3 that occurs while the patient is on dosing at 
300 mg every 2 weeks or 150 mg per week, then dosing of a patient with 
volanesorsen will be stopped permanently. Platelet count will be 
monitored daily until 2 successive values show improvement then 
monitored every 2-3 days until platelet count is stable. 
To increase 
platelet count 
monitoring for 
safety purposes 
Section 8.6.3 
Stopping Rules for 
Platelet Count 
Results 
Administration of steroids is recommended for patients whose platelet 
count is less than 25,000/mm3.  Recovery in platelet count may be 
accelerated by administration of high dose steroids.  Treatment 
guidelines for immune thrombocytopenia (Provan et al. 2010) 
recommend Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 
1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or 
Methylprednisolone 30 mg/kg/day for 7 days (note: may require 
continuation with oral steroids after methylprednisolone). 
To provide added 
patient safety 
regarding platelet 
count reductions 
and treatment 
recommendations 
Section 8.6.3 
Stopping Rules for 
Platelet Count 
Results 
Table 2 Actions in Patients with Low Platelet Count 
Platelet 
Count on 
Rx 
Drug Dose 
Monitoring 
Normal 
range, 
> 140K/mm3 
No action 
Monitor every 
2 weeks 
100K-
140K/mm3 
No action 
Closer observation 
Monitor every one 
week 
75K-
100K/mm3 
Reduce dose frequency to 
300mg every 2 weeks or 
reduce dose to 150 mg weekly 
Closer observation 
Monitor every one 
week 
50K-
75K/mm3 
Dose pause 
When platelet count returns to 
> 100K/mm3 restart dosing at 
dose frequency of 300 mg 
every 2 weeks or 150 mg 
weekly only if approved by 
Sponsor Medical Monitor 
Closer observation 
Monitor every 
2-3 days until 2 
successive values 
show improvement 
Consider 
discontinuation of 
antiplatelet 
agents/NSAIDS/antic
oagulant medication 
25K-
50K/mm3 
If occurs while on dose of 
300 mg every 2 weeks or 
150 mg every week then 
permanently discontinue Study 
Drug, otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at 
dose frequency of 300 mg 
every 2 weeks or 150 mg 
weekly only if approved by 
Sponsor Medical Monitor  
Closer observation 
Monitor daily until 
2 successive values 
show improvement 
then monitor every 
2-3 days until platelet 
count stable 
Discontinue 
antiplatelet 
agents/NSAIDS/antic
oagulant medication 
while platelet count 
< 50K/mm3 if possible 
 
To provide added 
patient safety 
regarding platelet 
count reductions, 
ISIS 304801 dose 
exposure, and 
treatment 
recommendations 
 


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Protocol Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping Rules for 
Platelet Count 
Results Continued 
Table 2 Actions in Patients with Low Platelet Count Continued 
< 25K/mm3 
Permanently discontinue Study 
Drug 
Closer observation: 
Monitor daily until 
2 successive values 
show improvement 
then monitor every 
2-3 days until platelet 
count stable. 
Steroids 
recommended* 
Consider need for 
hospitalization and 
referral to 
hematologist 
Discontinue 
antiplatelet 
agents/NSAIDS/antic
oagulant medication 
while platelet count 
< 50K/mm3 if possible 
* 
Recovery in platelet count may be accelerated by administration of 
high dose steroids.  Treatment guidelines for immune 
thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 
40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note: may require continuation with oral 
steroids after methylprednisolone) 
 
Section 8.1 
Volanesorsen 
Administration 
Patients entering this ISIS 304801-CS7 study on a reduced dose or dose 
frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or –CS16), will receive a reduced 
dose or dose frequency of volanesorsen for continued safety or tolerability 
as outlined in Sections 8.5 and 8.6.  Patients entering this CS7 study 
having dose or dose frequency reduced in the CS16 index study after 
13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, 
can receive the 300 mg once weekly dose of volanesorsen. 
To allow patients 
to receive a 
suitable dose or 
dose frequency 
of volanesorsen, 
based on safety/ 
tolerability or 
non-safety/ 
tolerability dosing 
rules  
 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of extended dosing with volanesorsen 
(volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center, open-label extension study of ISIS 304801-CS6 and 
ISIS 304801-CS16.  All patients will receive volanesorsen 300 mg once per 
week for 52 weeks.  Dietary counseling will be reinforced at intervals 
throughout the treatment and follow-up period.  Following the Week 52 visit, 
patients will enter a 13-week post-treatment evaluation period. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and 
Investigator judgement.  Patients who are enrolled in ISIS 304801-CS16 
must also meet the following criteria in order to enter into the Extension 
Study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of at least 1 of the 
following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 study 
4. 
Able and willing to participate in a 65-week study 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration 


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria: 
1. 
Have any new condition or worsening of existing condition which in 
the opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. 
Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6- and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies which included a subset of patients with FCS.  This is an 
extension to the ISIS 304801-CS6 and ISIS 304801-CS16 index studies.  
Only the subset of patients from ISIS 304801-CS16 with FCS diagnosis may 
enter the Extension Study.  (Please refer to inclusion criteria #3, above) 
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A.  A 52-week 
treatment period during which volanesorsen will be administered as 
a once weekly SC injection 
• 
A 13-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the extension study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter the 13-week post-treatment 
evaluation period. 


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PROTOCOL SYNOPSIS Continued 
Safety and Tolerability Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an extension study to 
the double-blind placebo controlled ISIS 304801-CS6 and ISIS 304801-CS16 
index studies. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
QUALIFICATION 
PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD assessments 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OLE 
Open Label Extension 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of extended dosing with 
volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an open 
label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of 
February 29, 2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of 
major bleeding or clinically-relevant non-major bleeding and had Study Drug paused as per the 
monitoring and stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered 
following suspension of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label extension to the Phase 3 study of volanesorsen in patients with FCS 
(ISIS 304801-CS6 or ISIS 304801-CS16).  Up to approximately 70 patients will receive 300 mg 
once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
• A qualification period of up to 2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A. 
• A 52-week treatment period during which volanesorsen will be administered as a once 
weekly SC injection 
• A 13-week post-treatment evaluation period 
Please refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Qualification 
A period of up to 2 weeks is given to complete qualification assessments outlined in the 
Schedule of Procedures (Appendix A). 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule or Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 2 Study Center visits on 
Weeks 58 and 65. 
3.5 
End of Study 
The End-of-Study is last patient, last visit. 


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3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open label study are performed.  During the 
qualification period, the eligibility of the patient to continue in the extension study will be 
determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may be 
used for qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient 
identification number will be used to identify the patient throughout the extension trial and must 
be used on all study documentation related to that patient.  The patient identification number 
must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled after all qualification assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No patient 
may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index studies) with 
an acceptable safety profile, per Sponsor and Investigator judgement.  Patients who are 


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enrolled in ISIS 304801-CS16 must also meet the following criteria in order to enter into 
the Extension Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of at least 1 of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤ 20% of normal 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 study. 
4. Able and willing to participate in a 65-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 


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6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the extension study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 2.5, 
4, 6, 8, 10, 12, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 40, 42, 44, 46, 48, 50, 54, 56, and 58 
may be conducted by a home healthcare nurse.  Approval for study procedures to be conducted 
by a home healthcare nurse on other outpatient visit days will require prior approval by the 
Sponsor.  Patients must be fasted prior to drawing all blood samples and samples drawn locally 
should also be sent to the central laboratory for analysis whenever possible.  Every effort should 
be made to ensure the previous week’s dose is given 7 days prior to a scheduled clinic visit.  
Dosing instructions and training will be provided to the patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.3 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 


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Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.4 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the 13-week 
post-treatment evaluation period.  This period consists of 4 Study Center visits on Weeks 54, 56, 
58 and 65 as outlined in the Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and determined not to have met a stopping rule before dosing 
can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
All platelet count results will be promptly reviewed by the Investigator to ensure that the count 
has not met the stopping rule and to determine whether the rate of decline is suggestive that the 
patient could be approaching the dose pause rule of 75,000/mm3. 
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 


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6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 rollover patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 


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6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.2.10 
Lipoprotein Lipase Activity Sample Collection 
Lipoprotein lipase (LPL) activity will be measured in ISIS 304801-CS16 rollover patients if 
needed for study qualification.  In brief, fasted patients will be given a low intravenous dose of 
heparin.  A blood sample will be drawn prior to and at 10 or 15 minutes after the heparin 
administration for measurement of LPL activity as per instructions provided to the Investigator. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent* or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 


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For female patients: 
• Using one or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
*Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 


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7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
300 mg injection once weekly for Weeks 1-52.  Patients entering this ISIS 304801-CS7 study on 
a reduced dose or dose frequency of Study Drug (volanesorsen), for safety or tolerability reasons 
in their index study (ISIS 304801-CS6 or –CS16), will receive a reduced dose or dose frequency 
of volanesorsen for continued safety or tolerability as outlined in Sections 8.5 and 8.6.  Patients 
entering this CS7 study having dose or dose frequency reduced in the CS16 index study after 
13 weeks of treatment, as outlined in CS16 Amendment 4 Section 8.7, can receive the 300 mg 
once weekly dose of volanesorsen. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 


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For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  Reduction in dose or dose frequency 
may also be initiated as noted in Section 8.7.  If any of the stopping criteria described below 
(refer to Sections 8.6.1 to 8.6.3) are met, the patient will be dose paused or permanently 
discontinued (as described in the stopping criterion concerned) from further treatment with 
volanesorsen, and evaluated fully as outlined below and in consultation with the Sponsor 
Medical Monitor or appropriately qualified designee, and will be followed up in accordance with 
Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 


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(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
Actions to be taken in the event of reduced platelet count are shown in Table 2 in Section 8.6.3. 
Additional lab tests will be determined by the Sponsor Medical Monitor or designee in 
consultation with the Investigator.  
Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 


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8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 


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If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1 week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 


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• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 


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8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 2 below. 
In the event of a platelet count less than 75,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor.  
In the event of any platelet count less than 25,000/mm3, or a platelet count less than 50,000/mm3 
that occurs while the patient is on dosing at 300 mg every 2 weeks or 150 mg every week then 
dosing of a patient with volanesorsen will be stopped permanently. Platelet count will be 
monitored daily until 2 successive values show improvement then monitored every 2-3 days until 
platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 
0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 30 mg/kg/day for 7 days  
(note: may require continuation with oral steroids after methylprednisolone). 
In the event of a platelet count less than 75,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered to 
≥ 100,000/mm3.  If dosing is continued it should be at a reduced dose frequency of 300 mg every 
2 weeks or a reduced dose of 150 mg per week (refer to Section 8.7).  The suitability of the 
patient for continued dosing will be determined by the Investigator in consultation with the Study 
Medical Monitor and will be based on factors such as the original rate of decline in the patient’s 
platelet count, whether any bleeding events were experienced by the patient, and the speed of 
recovery of platelet count upon holding of dosing. 


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If after the first dosing rechallenge the platelet count again falls below 75,000/mm3, then dosing 
of the patient must be held until the platelet count again returns to at least 100,000/mm3.  The 
suitability of the patient for continued dosing and the need for any further modification to 
treatment schedule or dose (refer to Section 8.7) will be re-examined by the Investigator in 
consultation with the Study Medical Monitor based on (at least) the factors mentioned above. 
If after the second rechallenge the platelet count falls below 75,000/mm3 and is subsequently 
confirmed (see Section 8.5), dosing with volanesorsen will be stopped permanently.  The 
follow-up schedule for any events meeting this stopping criterion will be determined by the 
Investigator in consultation with the Study Medical Monitor. 
Following a rechallenge platelet count should be tested every week until count is stable. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
 
 
 


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Table 2 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every one week 
75K-100K/mm3 
Reduce dose frequency to 300 mg every 
2 weeks or reduce dose to 150 mg weekly 
Closer observation 
Monitor every one week 
50K-75K/mm3 
Dose pause 
When platelet count returns to >100K/mm3 
restart dosing at dose frequency of 300 mg 
every 2 weeks or 150 mg weekly only if 
approved by Sponsor Medical Monitor 
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/NSAIDS/ 
anticoagulant medication 
25K-50K/mm3 
If occurs while on dose of 300 mg every 
2 weeks or 150 mg every week then 
permanently discontinue Study Drug, 
otherwise dose pause. 
When platelet count returns to 
> 100K/mm3 restart dosing at dose 
frequency of 300 mg every 2 weeks or 
150 mg weekly only if approved by 
Sponsor Medical Monitor  
Closer observation 
Monitor daily until 2 successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
< 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until two successive 
values show improvement then 
monitor every 2-3 days until 
platelet count stable 
Steroids recommended* 
Consider need for hospitalization 
and referral to hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet count 
< 50K/mm3 if possible 
* 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note: may require continuation with oral steroids after methyl prednisolone) 
 
8.7 
Adjustment of Dose Frequency 
Dose adjustments for platelet count reduction must be made in accordance with Section 8.6.3 and 
Table 2 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose or dose 
frequency will be allowed for safety and tolerability.  Any proposed adjustment to treatment 
schedule must be discussed with, and approved by, the Study Medical Monitor prior to initiation.  
Up to 2 adjustments in the treatment schedule may be allowed. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 


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8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be strongly encouraged to 
attend applicable landmark visits at Weeks 12, 13, 25, 26, and 51, 52 (calculated based on the 
time elapsed since Day 1) to collect fasting lipid panels and conduct safety assessments in 
accordance with the schedule of procedures in Appendix A.  Any patient who discontinues 
treatment after Week 44 should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last dose of Study Drug, in 
addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to undergo a final follow-up visit (Week 65, see Appendix A) prior 
to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 


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• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 


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Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 


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Table 3 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
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• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 


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9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen e.g., 
confirmation by positive rechallenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 


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• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 


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9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 


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9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are  
defined as the average of Week 51 (Day 351) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 


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• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints  
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an extension study to the double-blind, 
placebo-controlled ISIS 304801-CS6 and ISIS 304801-CS16 studies.  Approximately 70 patients 
may be eligible to enroll into this study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 evaluable PK sample collected, analyzed, and reported. 


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10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient:  ISIS 304801-CS6 or 
ISIS 304801-CS16 index study baseline and the baseline in this open label study, which is 
defined as the average of Day 1 pre-dose assessment and the last measurement prior to Day 1 
(e.g., qualification assessments or assessments from final visit of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline for safety will be the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the extension 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this OLE study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 
will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 
All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
studies.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index studies. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 


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All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index studies, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index studies. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index studies. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index studies. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index studies.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index studies for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group of the index studies. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification by their prior treatment in Study 
ISIS 304801-CS6 and ISIS 304801-CS16 and IM status. 


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For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open label extension 
(OLE) study from the intensive PK subgroup, following a single dose (i.e., single-dose PK) or 
multiple doses (i.e., steady-state PK), depending on their earlier treatment in the index studies.  
On Week 1 Day 1 of the OLE study, patients who received placebo in the index study will 
receive the first treatment of volanesorsen (single-dose PK), while patients who received 
volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these 
patients reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time 
taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under 
the plasma concentration-time curve from time zero to 24 hours (AUC0-24hr) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration 
(CL0-24hr /F0-24hr) will be calculated from CL0-24hr /F0-24hr = Actual Dose/AUC0-24hr.  Mean 
residence time (MRT) from time zero to 24 hours after the SC administration will be calculated 
from the equation, MRT0-24hr = AUMC0-24hr /AUC0-24hr, where AUMC0-24hr is the area under the 
moment plasma concentration-time curve from time zero to 24 hours after the SC administration.  
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 and study day.  
Subject ADA status (positive/negative or not evaluable) for all evaluable patients, along with the 
study day associated with the first positive IM status emerged (Tfirst, i.e., onset of ADA 
development), the last positive IM status observed (Tlast), the duration of ADA response (number 
of days between Tfirst and Tlast) if appropriate, the last ADA sample collection day, and subject - 
peak titer if applicable, will be listed by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16  study day.  Subjects with positive anti-volanesorsen antibody status may be 
further classified (when applicable) as being either ‘persistent’, ‘transient’, or ‘not determinable’, 
if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16.  Furthermore, onset, duration, and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 


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Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 


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occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 


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Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 


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To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 


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13. 
REFERENCES 
Altmann KH, Fabbrot D, Dean NM, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev. Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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Amendment 4 
Protocol 
6 June 2016 
 
61 
Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705.  
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


ISIS 304801-CS7 
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14. 
APPENDICES 
 
 
 


ISIS 304801-CS7 
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6 June 2016 
 
63 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
 


ISIS 304801-CS7 
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64 
Appendix A Schedule of Procedures 
Study Period 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk  
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40  
&  
42 
Wk 
44 
Wk 
46  
&  
48 
Month 12 
Wk54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to -
7 
1 
2 
11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
&  
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X Xk 
Xk Xk 
Xk 
Xk 
Xk 
Xk 
X 
Xk 
Xk 
Xk 
Xk 
X 
Xk 
Xk 
Xk 
X 
Xk 
Xk 
Xk 
Xk 
X 
Xk 
Xk 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
Echocardiography 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
 
 
 
 
 
Xl 
 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC with Differentialb 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Coagulation (aPTT, PT, INR) 
PG 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
hsCRP, HbA1c, FPG, and 
de-lipidated free glycerol 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - Volanesorsen 
 
Xm 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Archived Serum & Plasma 
Samplese 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 


ISIS 304801-CS7 
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Amendment 4 
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6 June 2016 
 
65 
Appendix A Schedule of Procedures Continued 
Study Period 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
2.5 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
10 
Month 3 
Wk 
15 
& 
17 
Wk 
19 
Wk 
21 
& 
23 
Month 6 
Wk 
28 
& 
30 
Wk 
32 
Wk 
34 
& 
36 
Wk 
38 
Wk 
40 
& 
42 
Wk 
44 
Wk 
46 
& 
48 
Month 12 
Wk 
54 
& 
56 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
50 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
11 
22 36 
50 
64 
78 
85 
99 
& 
113 
127 
141 
& 
155 
169 
176 
190 
& 
204 
218 
232 
& 
246 
260 
274 
& 
288 
302 
316 
& 
330 
344 
358 
372 
& 
386 
400 449 
Visit Window+/- Days 
0 
0 
0 
3 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
7 
7 
Urinalysisc 
X 
Xn 
 
 
X 
 
X 
 
 
Xn 
 
Xn 
 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
 
Xn 
 
Xn 
Xn 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
Genetic testing for FCS 
diagnosis (if not available in 
medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Postheparin Lipoprotein 
Lipase activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC 
Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Food/Drink Diary (quarterly)i 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Diet/Alcohol Counselingj 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Qualification procedures performed (Please refer to Section 4.1) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1-week and determined not to have met a stopping rule before dosing can continue.  If there is no reportable platelet count within 14 days of the last 
platelet count, the Investigator will contact the patient to hold dosing until a new platelet count is obtained and reviewed.  All platelet count results will be 
promptly reviewed by the Investigator to ensure that the count has not met the stopping rule and to determine whether the rate of decline is suggestive that 
the patient could be approaching the dose pause rule of 75,000/mm3.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion 
to the Sponsor 


ISIS 304801-CS7 
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6 June 2016 
 
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Appendix A Schedule of Procedures Continued 
Legend Text Continued 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (ISIS 304801-CS16 rollover patients) and repeated 
at Week 52 (Please refer to Section 6.2.2.2) 
g 
Genetic testing can be conducted for study qualification (ISIS 304801-CS16 rollover patients); genetic testing will only be conducted if allowed in the 
geographic region and only after the patient has given specific written informed consent for genetic testing 
h 
Post-heparin lipoprotein lipase activity can be conducted for study qualification (ISIS 304801-CS16 rollover patients; please refer to Section 6.2.10) 
i 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
j 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
k 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
l 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
m 
Full or abbreviated PK profile (see Appendix C) 
n 
Expanded urinalysis (see Appendix B) 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
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Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
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Amendment 4 
Protocol 
6 June 2016 
 
68 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
69 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
70 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
71 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
72 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
73 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 4 
Protocol 
6 June 2016 
 
74 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
Adverse Event 
Mild 
Moderate 
Severe 
Urine 
Proteinuria 
Adults 
1 + proteinuria; 
2+ proteinuria; 
Urinary protein 
g/24 hrs; 
urinary protein < 1.0 g/24 hrs 
urinary protein 1.0 - 3.4 g/24 hrs; 
Children 
-
Urine PIC (Protein/Creatinine) 
Urine P/C >1.9 
ratio 0.5 - 1.9 
Gross hematuria; transfusion, 
Asymptomatic; clinical or diagnostic 
IV medications or 
Symptomatic; urinary catheter or hospitalization indicated; 
Hematuria 
observations only; intervention not 
bladder irrigation indicated 
elective endoscopic, radiologic 
indicated 
or operative intervention 
indicated 
tGrading for this parameter is derived from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept 2007 
*Grading for this parameter is derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, Nov 2014 
tModified for consistency with the ADA and Endocrine Society Guidelines (Seaquist ER, Anderson J, Childs B, et al. 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. 
Diabetes Care 2013;36: 1384-95) 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 3 –9 May 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 3
Protocol 
 
9 May 2016
 
2 
 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 3 – 9 May 2016 
 
 
Protocol History: 
Original Protocol: 
 
28 August 2015 
Protocol Amendment 1: 
2 February 2016 
Protocol Amendment 2: 
22 April 2016 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
______________________ 
M.D., M.B.A. 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 3 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
9 May 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome 
(FCS) 
Amendment: 
Amendment 3 
Date:  
 
9 May 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Extension Study of Volanesorsen Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS)”, dated 9 May 2016, and agree to conduct the study 
as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................11 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................14 
STUDY GLOSSARY ...................................................................................................................15 
1. 
OBJECTIVES .....................................................................................................................17 
2. 
BACKGROUND AND RATIONALE ..............................................................................17 
2.1 
Overview of Disease ......................................................................................................17 
2.2 
Therapeutic Rationale ....................................................................................................18 
2.3 
Volanesorsen ..................................................................................................................19 
2.3.1 
Mechanism of Action .............................................................................................19 
2.3.2 
Chemistry ...............................................................................................................20 
2.3.3 
Preclinical Experience ............................................................................................21 
2.3.4 
Clinical Experience ................................................................................................22 
2.4 
Rationale for Dose and Schedule of Administration .....................................................23 
3. 
EXPERIMENTAL PLAN ..................................................................................................24 
3.1 
Study Design ..................................................................................................................24 
3.2 
Number of Study Centers ..............................................................................................24 
3.3 
Number of Patients ........................................................................................................24 
3.4 
Overall Study Duration and Follow-up .........................................................................24 
3.4.1 
Qualification ...........................................................................................................24 
3.4.2 
Treatment ................................................................................................................24 
3.4.3 
Post-Treatment .......................................................................................................24 
3.5 
End of Study ..................................................................................................................24 
3.6 
Data and Safety Monitoring Board ................................................................................25 
4. 
PATIENT ENROLLMENT ...............................................................................................25 
4.1 
Qualification ..................................................................................................................25 
4.2 
Enrollment .....................................................................................................................25 
5. 
PATIENT ELIGIBILITY ..................................................................................................25 
5.1 
Inclusion Criteria ...........................................................................................................25 
5.2 
Exclusion Criteria ..........................................................................................................26 
6. 
STUDY PROCEDURES ....................................................................................................27 
6.1 
Study Schedule ..............................................................................................................27 
6.1.1 
Qualification ...........................................................................................................27 
6.1.2 
Treatment Period ....................................................................................................27 
6.1.3 
Pharmacokinetic (PK) Subgroup ............................................................................27 
6.1.4 
Post-Treatment Period ............................................................................................28 
6.2 
Additional Study Assessments .......................................................................................28 
6.2.1 
Laboratory Assessments .........................................................................................28 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
6 
6.2.2 
Physical Exams and Vital Signs .............................................................................28 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................28 
6.2.2.2 
Lipemia Retinalis .............................................................................................28 
6.2.3 
Echocardiography ...................................................................................................29 
6.2.4 
ECG ........................................................................................................................29 
6.2.5 
MRI ........................................................................................................................29 
6.2.6 
Quality of Life Assessments ...................................................................................29 
6.2.7 
Disease Symptom Diary .........................................................................................29 
6.2.8 
Diet Monitoring ......................................................................................................29 
6.2.9 
Family History ........................................................................................................29 
6.2.10 
Lipoprotein Lipase Activity Sample Collection .....................................................30 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................30 
6.3.1 
Contraception Requirements ..................................................................................30 
6.3.2 
Other Requirements ................................................................................................31 
7. 
STUDY DRUG ....................................................................................................................31 
7.1 
Volanesorsen Description ..............................................................................................31 
7.2 
Packaging and Labeling .................................................................................................32 
7.3 
Study Drug Accountability ............................................................................................32 
8. 
TREATMENT OF PATIENTS .........................................................................................32 
8.1 
Volanesorsen Administration ........................................................................................32 
8.2 
Other Protocol-Required Drugs .....................................................................................32 
8.3 
Other Protocol-Required Treatment Procedures ............................................................32 
8.4 
Treatment Precautions ...................................................................................................32 
8.5 
Safety Monitoring Rules ................................................................................................33 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................33 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................34 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................34 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................34 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................35 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........35 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................35 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................36 
8.5.9 
Acute Pancreatitis ...................................................................................................37 
8.6 
Stopping Rules ...............................................................................................................37 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................37 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................38 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................38 
8.7 
Adjustment of Dose Frequency .....................................................................................39 
8.8 
Discontinuation of Study Treatment ..............................................................................39 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................40 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
7 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .40 
8.9 
Withdrawal of Patients from the Study ..........................................................................40 
8.10 
Concomitant Therapy and Procedures ...........................................................................41 
8.10.1 
Concomitant Therapy .............................................................................................41 
8.10.2 
Concomitant Procedures .........................................................................................41 
8.11 
Treatment Compliance ...................................................................................................42 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................42 
9.1 
Sponsor Review of Safety Information .........................................................................42 
9.2 
Regulatory Requirements ..............................................................................................42 
9.3 
Definitions .....................................................................................................................43 
9.3.1 
Adverse Event ........................................................................................................43 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................43 
9.3.3 
Serious Adverse Event (SAE) ................................................................................43 
9.4 
Monitoring and Recording Adverse Events ...................................................................44 
9.4.1 
Serious Adverse Events ..........................................................................................44 
9.4.2 
Non-Serious Adverse Events ..................................................................................44 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................44 
9.4.3.1 
Relationship to the Study Drug ........................................................................44 
9.4.3.2 
Severity ............................................................................................................45 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................45 
9.4.3.4 
Treatment Given for Adverse Event ................................................................45 
9.4.3.5 
Outcome of the Adverse Event ........................................................................46 
9.4.4 
Adjudication Committees .......................................................................................46 
9.5 
Procedures for Handling Special Situations ..................................................................46 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................46 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............47 
9.5.3 
Dosing Errors .........................................................................................................47 
9.5.4 
Contraception and Pregnancy .................................................................................47 
10. STATISTICAL CONSIDERATIONS ..............................................................................48 
10.1 
Study Endpoints .............................................................................................................48 
10.1.1 
Efficacy Endpoints .................................................................................................48 
10.1.2 
Safety Endpoints .....................................................................................................49 
10.2 
Sample Size ....................................................................................................................49 
10.3 
Populations .....................................................................................................................49 
10.4 
Definition of Baseline ....................................................................................................49 
10.5 
Interim Analysis .............................................................................................................50 
10.6 
Planned Methods of Analysis ........................................................................................50 
10.6.1 
Demographic and Baseline Characteristics ............................................................50 
10.6.2 
Safety Analysis .......................................................................................................50 
10.6.3 
Efficacy Analysis ...................................................................................................51 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
8 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................51 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................51 
10.6.4.2 
Immunogenicity Analysis ................................................................................52 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................53 
11.1 
Informed Consent ..........................................................................................................53 
11.2 
Ethical Conduct of the Study .........................................................................................53 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................53 
11.4 
Patient Confidentiality ...................................................................................................54 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................54 
12.1 
Protocol Amendments ....................................................................................................54 
12.2 
Study Termination .........................................................................................................54 
12.3 
Study Documentation and Storage ................................................................................54 
12.4 
Study Monitoring ...........................................................................................................55 
12.5 
Language ........................................................................................................................56 
12.6 
Compensation for Injury ................................................................................................56 
13. REFERENCES ....................................................................................................................57 
14. APPENDICES .....................................................................................................................59 
Appendix A 
Schedule of Procedures ....................................................................................60 
Appendix B 
List of Laboratory Analytes .............................................................................64 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................66 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......68 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics ........................................................ 32 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence .................................................................................. 42 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 18 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides   
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 20 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 22 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
3 
Amendment Date: 
9 May 2016 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 2 dated 22 April 2016: 
1. To add language that any case of a platelet count ≤ 50,000/mm3 should be reported in an 
expedited fashion to the Sponsor. 
2. To add language regarding the frequency of obtaining platelet counts after a Study Drug 
dose pause and subsequent rechallenge. 
3. To add language that any unreportable platelet count result must be rechecked and 
determined not to have met a stopping rule before dosing can continue. 
Minor administrative changes or corrections (not included in the list of changes) have been made 
throughout the protocol in order to improve the overall clarity of the protocol but these changes 
do not impact the study design. 
The following table provides a summary list of changes to the protocol: 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
10 
Protocol Section 
Description of Change 
Rationale 
Section 6.2.1 
Laboratory Assessments 
Section 8.5.2 
Safety Monitoring for 
Platelet Count Results 
Appendix A Schedule 
of Procedures 
Any case of a platelet count ≤ 50,000/mm3 should 
be reported in an expedited fashion to the 
Sponsor 
To ensure that Sponsor is 
aware in a timely fashion of 
platelet counts performed in 
local lab that have met the 
rule for dose pause 
Section 8.6.3  
Stopping Rules for Platelet 
Count Results 
Following a rechallenge platelet count should be 
tested every week until count is stable 
To more closely monitor 
platelet levels following a 
rechallenge 
Section 6.2.1 
Laboratory Assessments 
Section 8.6.3 
Stopping Rules for Platelet 
Count Results  
Appendix A Schedule 
of Procedures 
Any unreportable platelet count result must be 
rechecked and determined not to have met a 
stopping rule before dosing can continue 
To provide added patient 
safety regarding platelet 
stopping rules 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
11 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of extended dosing with volanesorsen 
(volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center, open-label extension study of ISIS 304801-CS6 and 
ISIS 304801-CS16.  All patients will receive volanesorsen 300 mg once per 
week for 52 weeks.  Dietary counseling will be reinforced at intervals 
throughout the treatment and follow-up period.  Following the Week 52 visit, 
patients will enter a 13-week post-treatment evaluation period. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed 
and dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 
(index studies) with an acceptable safety profile, per Sponsor and 
Investigator judgement.  Patients who are enrolled in ISIS 304801-CS16 
must also meet the following criteria in order to enter into the Extension 
Study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of at least 1 of the 
following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 study 
4. 
Able and willing to participate in a 65-week study 
5. 
Satisfy 1 of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent*, or if engaged in 
sexual relations of child-bearing potential, patient is using an 
acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last 
dose of Study Drug administration 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
12 
PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria: 
1. 
Have any new condition or worsening of existing condition which in 
the opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. 
Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6- and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies which included a subset of patients with FCS.  This is an 
extension to the ISIS 304801-CS6 and ISIS 304801-CS16 index studies.  
Only the subset of patients from ISIS 304801-CS16 with FCS diagnosis may 
enter the Extension Study.  (Please refer to inclusion criteria #3, above) 
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A.  A 52-week 
treatment period during which volanesorsen will be administered as 
a once weekly SC injection 
• 
A 13-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the extension study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter the 13-week post-treatment 
evaluation period. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
13 
PROTOCOL SYNOPSIS Continued 
Safety and Tolerability Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an extension study to 
the double-blind placebo controlled ISIS 304801-CS6 and ISIS 304801-CS16 
index studies. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
QUALIFICATION 
PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD assessments 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OLE 
Open Label Extension 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of extended dosing with 
volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an open 
label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of February 29, 
2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of major bleeding 
or clinically-relevant non-major bleeding and had Study Drug paused as per the monitoring and 
stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered following suspension 
of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label extension to the Phase 3 study of volanesorsen in patients with FCS 
(ISIS 304801-CS6 or ISIS 304801-CS16).  Up to approximately 70 patients will receive 300 mg 
once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
• A qualification period of up to 2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A. 
• A 52-week treatment period during which volanesorsen will be administered as a once 
weekly SC injection 
• A 13-week post-treatment evaluation period 
Please refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Qualification 
A period of up to 2 weeks is given to complete qualification assessments outlined in the 
Schedule of Procedures (Appendix A). 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule or Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 2 Study Center visits on 
Weeks 58 and 65. 
3.5 
End of Study 
The End-of-Study is last patient, last visit. 


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3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open label study are performed.  During the 
qualification period, the eligibility of the patient to continue in the extension study will be 
determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may be 
used for qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient 
identification number will be used to identify the patient throughout the extension trial and must 
be used on all study documentation related to that patient.  The patient identification number 
must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled after all qualification assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No patient 
may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index studies) with 
an acceptable safety profile, per Sponsor and Investigator judgement.  Patients who are 


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enrolled in ISIS 304801-CS16 must also meet the following criteria in order to enter into 
the Extension Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of at least 1 of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤ 20% of normal 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 study. 
4. Able and willing to participate in a 65-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 


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6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the extension study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 4, 8, 
12, 16, 19, 22, 25, 29, 32, 35, 41, 44, 47, 51, and 58 may be conducted by a home healthcare 
nurse .  Approval for study procedures to be conducted by a home healthcare nurse on other 
outpatient visit days will require prior approval by the Sponsor.  Patients must be fasted prior to 
drawing all blood samples and samples drawn locally must be sent to the central laboratory for 
analysis.  Every effort should be made to ensure the previous week’s dose is given 7 days prior 
to a scheduled clinic visit.  Dosing instructions and training will be provided to the patient where 
applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.3 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 


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Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.4 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the 13-week 
post-treatment evaluation period.  This period consists of 2 Study Center visits on Weeks 58 and 
65 as outlined in the Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional 
sample should be collected in parallel and analyzed locally.  In the event that both the central and 
local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample 
must be repeated within 1-week and determined not to have met a stopping rule before dosing 
can continue. 
Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 rollover patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
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6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary 
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 


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6.2.10 
Lipoprotein Lipase Activity Sample Collection 
Lipoprotein lipase (LPL) activity will be measured in ISIS 304801-CS16 rollover patients if 
needed for study qualification.  In brief, fasted patients will be given a low intravenous dose of 
heparin.  A blood sample will be drawn prior to and at 10 or 15 minutes after the heparin 
administration for measurement of LPL activity as per instructions provided to the Investigator. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent* or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using one or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 


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contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
*Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 
 
 


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Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
injection once weekly for Weeks 1-52. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 


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8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
below (refer to Sections 8.6.1 to 8.6.3) are met, the patient will be permanently discontinued 
from further treatment with volanesorsen, evaluated fully as outlined below and in consultation 
with the Sponsor Medical Monitor or appropriately qualified designee, and will be followed up 
in accordance with Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 


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(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
In the event of any significant fall in platelet count, or if the absolute platelet count is 
75,000/mm3 or less, then the patient’s platelet counts should be monitored more frequently.  The 
frequency of monitoring and additional lab tests will be determined by the Sponsor Medical 
Monitor or designee in consultation with the Investigator.  
Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the 
Sponsor (See also Stopping Rules Section 8.6.3). 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 


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8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 


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If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1 week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 


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• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 


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8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rules for Platelet Count Results 
In the event of a platelet count less than 50,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor. 
In the event of a platelet count less than 50,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered to 
≥ 100,000/mm3.  The suitability of the patient for continued dosing and the need for any 
modification to treatment schedule (refer to Section 8.7) will be determined by the Investigator 
in consultation with the Study Medical Monitor and will be based on factors such as the original 
rate of decline in the patient’s platelet count, whether any bleeding events were experienced by 
the patient, and the speed of recovery of platelet count upon holding of dosing. 
If after the first dosing rechallenge the platelet count again falls below 50,000/mm3, then dosing 
of the patient must be held until the platelet count again returns to at least 100,000/mm3.  The 
suitability of the patient for continued dosing and the need for any further modification to 
treatment schedule or dose (refer to Section 8.7) will be re-examined by the Investigator in 
consultation with the Study Medical Monitor based on (at least) the factors mentioned above. 
If after the second rechallenge the platelet count falls below 50,000/mm3 and is subsequently 
confirmed (see Section 8.5), dosing with volanesorsen will be stopped permanently.  The 
follow-up schedule for any events meeting this stopping criterion will be determined by the 
Investigator in consultation with the Study Medical Monitor. 
Following a rechallenge platelet count should be tested every week until count is stable. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue. 


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Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
8.7 
Adjustment of Dose Frequency 
Dose adjustments, including dose interruptions, and/or decreasing the dose frequency will be 
allowed for safety and tolerability.  Any proposed adjustment to treatment schedule must be 
discussed with, and approved by, the Study Medical Monitor prior to initiation.  Up to 
2  adjustments in the treatment schedule may be allowed for patients that are unable to tolerate 
the once weekly dose (for example if platelet counts fall below 50,000/mm3 as described in 
Section 8.6.3).  If the patient remains stable after adjustment, they may be cautiously returned to 
the original once weekly regimen after consultation with the Study Medical Monitor. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 


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• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be strongly encouraged to 
attend applicable landmark visits at Weeks 12, 13, 25, 26, and 51, 52 (calculated based on the 
time elapsed since Day 1) to collect fasting lipid panels and conduct safety assessments in 
accordance with the schedule of procedures in Appendix A.  Any patient who discontinues 
treatment after Week 44 should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last dose of Study Drug, in 
addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to undergo a final follow-up visit (Week 65, see Appendix A) prior 
to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 


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encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 


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8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 


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aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 


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medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen e.g., 
confirmation by positive rechallenge test 


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• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 


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9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 


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Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 


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Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are  
defined as the average of Week 51 (Day 351) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 


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10.1.2 
Safety Endpoints  
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an extension study to the double-blind, 
placebo-controlled ISIS 304801-CS6 and ISIS 304801-CS16 studies.  Approximately 70 patients 
may be eligible to enroll into this study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 evaluable PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient:  ISIS 304801-CS6 or 
ISIS 304801-CS16 index study baseline and the baseline in this open label study, which is 
defined as the average of Day 1 pre-dose assessment and the last measurement prior to Day 1 
(e.g., qualification assessments or assessments from final visit of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
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baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline for safety will be the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the extension 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this OLE study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 
will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 
All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
studies.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index studies. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index studies, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index studies. 


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Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index studies. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index studies. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index studies.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index studies for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group of the index studies. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification by their prior treatment in Study 
ISIS 304801-CS6 and ISIS 304801-CS16 and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open label extension 
(OLE) study from the intensive PK subgroup, following a single dose (i.e., single-dose PK) or 
multiple doses (i.e., steady-state PK), depending on their earlier treatment in the index studies.  
On Week 1 Day 1 of the OLE study, patients who received placebo in the index study will 
receive the first treatment of volanesorsen (single-dose PK), while patients who received 
volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these 
patients reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time 


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taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under 
the plasma concentration-time curve from time zero to 24 hours (AUC0-24hr) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration 
(CL0-24hr /F0-24hr) will be calculated from CL0-24hr /F0-24hr = Actual Dose/AUC0-24hr.  Mean 
residence time (MRT) from time zero to 24 hours after the SC administration will be calculated 
from the equation, MRT0-24hr = AUMC0-24hr /AUC0-24hr, where AUMC0-24hr is the area under the 
moment plasma concentration-time curve from time zero to 24 hours after the SC administration.  
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 and study day.  
Subject ADA status (positive/negative or not evaluable) for all evaluable patients, along with the 
study day associated with the first positive IM status emerged (Tfirst, i.e., onset of ADA 
development), the last positive IM status observed (Tlast), the duration of ADA response (number 
of days between Tfirst and Tlast) if appropriate, the last ADA sample collection day, and subject - 
peak titer if applicable, will be listed by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16  study day.  Subjects with positive anti-volanesorsen antibody status may be 
further classified (when applicable) as being either ‘persistent’, ‘transient’, or ‘not determinable’, 
if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16.  Furthermore, onset, duration, and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 


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11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 


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11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 


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Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 


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The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 


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13. 
REFERENCES 
Altmann KH, Fabbrot D, Dean NM, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev. Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 
 
 


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14. 
APPENDICES 
 
 
 


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Appendix A 
Schedule of Procedures 
 
 


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Appendix A Schedule of Procedures 
Study Period 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3  
Wk 
16 
Wk 
19 
Wk 
22 
Month 6 
Wk 
29 
Wk 
32 
Wk 
35 
Wk 
38 
Wk 
41 
Wk 
44 
Wk 
47 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 1 
2 
22 
50 
78 
85 
106 
127 
148 
169 
176 
197 
218 
239 
260 
281 
302 
323 
351 
358 
400 
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
3 
3 
2 
2 
3 
3 
3 
3 
3 
3 
3 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
Xk 
Xk 
Xk 
Xk 
X 
Xk 
Xk 
Xk 
Xk 
X 
Xk 
Xk 
Xk 
X 
Xk 
Xk 
Xk 
Xk 
X 
Xk 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Physical Examination 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
Echocardiography 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
 
 
 
 
 
Xl 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
CBC with Differentialb 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
Coagulation (aPTT, PT, INR) 
PG 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
hsCRP, HbA1c, FPG, and de-lipidated 
free glycerol 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
Xm 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Archived Serum & Plasma Samplese 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 


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Appendix A Schedule of Procedures Continued 
Study Period 
Quala 
Treatment Period 
Post 
Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3 
Wk 
16 
Wk 
19 
Wk 
22 
Month 6 
Wk 
29 
Wk 
32 
Wk 
35 
Wk 
38 
Wk 
41 
Wk 
44 
Wk 
47 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 
50 
78 
85 
106 127 
148 
169 
176 
197 
218 
239 260 281 
302 
323 
351 
358 
400 449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
3 
3 
2 
2 
3 
3 
3 
3 
3 
3 
3 
2 
2 
7 
7 
Urinalysisc 
X 
Xn 
 
X 
X 
 
Xn 
 
Xn 
 
 
Xn 
 
Xn 
 
Xn 
 
Xn 
 
 
Xn 
Xn 
Xn 
Fundus Photographyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
Genetic testing for FCS diagnosis (if not 
available in medical history)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Postheparin Lipoprotein Lipase activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Food/Drink Diary (quarterly)i 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Diet/Alcohol Counselingj 
X 
X 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Qualification procedures performed (Please refer to Section 4.1) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are unreportable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1-week and determined not to have met a stopping rule before dosing can continue.  Any case of a platelet count ≤ 50,000/mm3 should be reported in 
an expedited fashion to the Sponsor 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
63 
Appendix A Schedule of Procedures Continued 
Legend Text Continued 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (ISIS 304801-CS16 rollover patients) and repeated 
at Week 52 (Please refer to Section 6.2.2.2) 
g 
Genetic testing can be conducted for study qualification (ISIS 304801-CS16 rollover patients); genetic testing will only be conducted if allowed in the 
geographic region and only after the patient has given specific written informed consent for genetic testing 
h 
Post-heparin lipoprotein lipase activity can be conducted for study qualification (ISIS 304801-CS16 rollover patients; please refer to Section 6.2.10) 
i 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
j 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
k 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
l 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
m 
Full or abbreviated PK profile (see Appendix C) 
n 
Expanded urinalysis (see Appendix B) 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
64 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
65 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other Assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
66 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
67 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
68 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
69 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
70 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 3 
Protocol 
9 May 2016 
 
71 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 2 –22 April 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304801-CS7 
Protocol 
CONFIDENTIAL 
ISIS 304801-CS7 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
Amendment2 
22 April 2016 
An Open-Label Extension Study ofVolanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Amendment 2- 22 April 2016 
Protocol History: 
Original Protocol: 
Protocol Amendment 1: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
M.D., M.B.A. 
28 August 2015 
2 February 2016 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 2 
Protocol 
22 April 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 2 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
22 April 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 2 
Protocol 
22 April 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome 
(FCS) 
Amendment: 
Amendment 2 
Date:  
 
22 April 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Extension Study of Volanesorsen Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS)”, dated 22 April 2016, and agree to conduct the 
study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 2 
Protocol 
22 April 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................12 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................15 
STUDY GLOSSARY ...................................................................................................................16 
1. 
OBJECTIVES .....................................................................................................................18 
2. 
BACKGROUND AND RATIONALE ..............................................................................18 
2.1 
Overview of Disease ......................................................................................................18 
2.2 
Therapeutic Rationale ....................................................................................................19 
2.3 
Volanesorsen ..................................................................................................................20 
2.3.1 
Mechanism of Action .............................................................................................20 
2.3.2 
Chemistry ...............................................................................................................21 
2.3.3 
Preclinical Experience ............................................................................................22 
2.3.4 
Clinical Experience ................................................................................................23 
2.4 
Rationale for Dose and Schedule of Administration .....................................................24 
3. 
EXPERIMENTAL PLAN ..................................................................................................25 
3.1 
Study Design ..................................................................................................................25 
3.2 
Number of Study Centers ..............................................................................................25 
3.3 
Number of Patients ........................................................................................................25 
3.4 
Overall Study Duration and Follow-up .........................................................................25 
3.4.1 
Qualification ...........................................................................................................25 
3.4.2 
Treatment ................................................................................................................25 
3.4.3 
Post-Treatment .......................................................................................................25 
3.5 
End of Study ..................................................................................................................25 
3.6 
Data and Safety Monitoring Board ................................................................................26 
4. 
PATIENT ENROLLMENT ...............................................................................................26 
4.1 
Qualification ..................................................................................................................26 
4.2 
Enrollment .....................................................................................................................26 
5. 
PATIENT ELIGIBILITY ..................................................................................................26 
5.1 
Inclusion Criteria ...........................................................................................................26 
5.2 
Exclusion Criteria ..........................................................................................................27 
6. 
STUDY PROCEDURES ....................................................................................................28 
6.1 
Study Schedule ..............................................................................................................28 
6.1.1 
Qualification ...........................................................................................................28 
6.1.2 
Treatment Period ....................................................................................................28 
6.1.3 
Pharmacokinetic (PK) Subgroup ............................................................................28 
6.1.4 
Post-Treatment Period ............................................................................................29 
6.2 
Additional Study Assessments .......................................................................................29 
6.2.1 
Laboratory Assessments .........................................................................................29 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 2 
Protocol 
22 April 2016 
 
6 
6.2.2 
Physical Exams and Vital Signs .............................................................................29 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................29 
6.2.2.2 
Lipemia Retinalis .............................................................................................29 
6.2.3 
Echocardiography ...................................................................................................29 
6.2.4 
ECG ........................................................................................................................30 
6.2.5 
MRI ........................................................................................................................30 
6.2.6 
Quality of Life Assessments ...................................................................................30 
6.2.7 
Disease Symptom Diary .........................................................................................30 
6.2.8 
Diet Monitoring ......................................................................................................30 
6.2.9 
Family History ........................................................................................................30 
6.2.10 
Lipoprotein Lipase Activity Sample Collection .....................................................30 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................31 
6.3.1 
Contraception Requirements ..................................................................................31 
6.3.2 
Other Requirements ................................................................................................32 
7. 
STUDY DRUG ....................................................................................................................32 
7.1 
Volanesorsen Description ..............................................................................................32 
7.2 
Packaging and Labeling .................................................................................................32 
7.3 
Study Drug Accountability ............................................................................................32 
8. 
TREATMENT OF PATIENTS .........................................................................................33 
8.1 
Volanesorsen Administration ........................................................................................33 
8.2 
Other Protocol-Required Drugs .....................................................................................33 
8.3 
Other Protocol-Required Treatment Procedures ............................................................33 
8.4 
Treatment Precautions ...................................................................................................33 
8.5 
Safety Monitoring Rules ................................................................................................33 
8.5.1 
Safety Monitoring for Liver Chemistry Tests ........................................................34 
8.5.2 
Safety Monitoring for Platelet Count Results ........................................................35 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................35 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................35 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................35 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........35 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................36 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................37 
8.5.9 
Acute Pancreatitis ...................................................................................................38 
8.6 
Stopping Rules ...............................................................................................................38 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................38 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................38 
8.6.3 
Stopping Rules for Platelet Count Results .............................................................39 
8.7 
Adjustment of Dose Frequency .....................................................................................40 
8.8 
Discontinuation of Study Treatment ..............................................................................40 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................40 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 2 
Protocol 
22 April 2016 
 
7 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .41 
8.9 
Withdrawal of Patients from the Study ..........................................................................41 
8.10 
Concomitant Therapy and Procedures ...........................................................................41 
8.10.1 
Concomitant Therapy .............................................................................................41 
8.10.2 
Concomitant Procedures .........................................................................................42 
8.11 
Treatment Compliance ...................................................................................................42 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................42 
9.1 
Sponsor Review of Safety Information .........................................................................42 
9.2 
Regulatory Requirements ..............................................................................................42 
9.3 
Definitions .....................................................................................................................43 
9.3.1 
Adverse Event ........................................................................................................43 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................44 
9.3.3 
Serious Adverse Event (SAE) ................................................................................44 
9.4 
Monitoring and Recording Adverse Events ...................................................................44 
9.4.1 
Serious Adverse Events ..........................................................................................44 
9.4.2 
Non-Serious Adverse Events ..................................................................................45 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................45 
9.4.3.1 
Relationship to the Study Drug ........................................................................45 
9.4.3.2 
Severity ............................................................................................................46 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................46 
9.4.3.4 
Treatment Given for Adverse Event ................................................................46 
9.4.3.5 
Outcome of the Adverse Event ........................................................................46 
9.4.4 
Adjudication Committees .......................................................................................47 
9.5 
Procedures for Handling Special Situations ..................................................................47 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................47 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............47 
9.5.3 
Dosing Errors .........................................................................................................48 
9.5.4 
Contraception and Pregnancy .................................................................................48 
10. STATISTICAL CONSIDERATIONS ..............................................................................49 
10.1 
Study Endpoints .............................................................................................................49 
10.1.1 
Efficacy Endpoints .................................................................................................49 
10.1.2 
Safety Endpoints .....................................................................................................49 
10.2 
Sample Size ....................................................................................................................50 
10.3 
Populations .....................................................................................................................50 
10.4 
Definition of Baseline ....................................................................................................50 
10.5 
Interim Analysis .............................................................................................................50 
10.6 
Planned Methods of Analysis ........................................................................................50 
10.6.1 
Demographic and Baseline Characteristics ............................................................51 
10.6.2 
Safety Analysis .......................................................................................................51 
10.6.3 
Efficacy Analysis ...................................................................................................51 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
8 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................52 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................52 
10.6.4.2 
Immunogenicity Analysis ................................................................................53 
11.  INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................53 
11.1 
Informed Consent ..........................................................................................................53 
11.2 
Ethical Conduct of the Study .........................................................................................54 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................54 
11.4 
Patient Confidentiality ...................................................................................................54 
12.  ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................55 
12.1 
Protocol Amendments ....................................................................................................55 
12.2 
Study Termination .........................................................................................................55 
12.3 
Study Documentation and Storage ................................................................................55 
12.4 
Study Monitoring ...........................................................................................................56 
12.5 
Language ........................................................................................................................56 
12.6 
Compensation for Injury ................................................................................................56 
13.  REFERENCES ....................................................................................................................57 
14.  APPENDICES .....................................................................................................................59 
Appendix A 
Schedule of Procedures ....................................................................................60 
Appendix B 
List of Laboratory Analytes .............................................................................64 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................66 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities ......68 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics ........................................................ 32 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence .................................................................................. 43 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 19 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides   
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 21 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 23 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
2 
Amendment Date: 
22 April 2016 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 Amendment 1 dated 02 February 2016: 
1. To modify the clinical experience safety language to reflect updated blinded safety data 
from ongoing studies. 
2. To indicate that the DSMB is independent. 
3. To revise the contraceptive requirements to state that abstinence is only acceptable as true 
abstinence, i.e., when it is in line with the preferred and usual lifestyle of the patient. 
4. To add lipoprotein lipase activity as a qualification assessment for ISIS 304801-CS16 
rollover patients. 
5. To add genetic testing as a qualification assessment for ISIS 304801-CS16 rollover 
patients. 
6. To increase the frequency of the pregnancy testing. 
7. To add hematology blood draws at Weeks 12, 16, 22, 25, 29, 35, 41, 47, and 51 to more 
frequently assess platelet counts. 
8. To allow blood sampling at Weeks 4, 8, 12, 16, 19, 22, 25, 29, 32, 35, 41, 44, 47, 51, and 
58 to be conducted by a home healthcare nurse. 
9. To allow blood sampling at the 24-hour PK blood draw to be conducted by a home 
healthcare nurse. 
10. To add language that each time a hematology lab is drawn and sent to the central 
laboratory for analysis, an additional sample should be collected in parallel and analyzed 
locally, to reduce the occurrence of unreportable hematology results. 
11. To provide guidance that the length of fasting should preferably not be more than 
12 hours. 


ISIS 304801-CS7 
CONFIDENTIAL
Amendment 2
Protocol
22 April 2016
10 
12. To update platelet monitoring rule language to allow for more frequent monitoring as
determined by the Sponsor Medical Monitor in consultation with the Investigator.
13. To add language to the safety monitoring for insulin, oral antidiabetic medication and
glucose that all patients, including those not on insulin, who use a glucometer should also
bring their glucometer and/or glucometer log printout to every clinic visit.
14. To clarify guidance on determining relatedness of a SUSAR.
Minor administrative changes or corrections (not included in the list of changes) have been made 
throughout the protocol in order to improve the overall clarity of the protocol but these changes 
do not impact the study design. 
The following table provides a summary list of changes to the protocol: 
Protocol Section 
Description of Change 
Rationale 
Section 2.3.4 Clinical 
Experience 
In the completed studies there have been no 
ISIS 304801 associated laboratory abnormalities 
suggestive of an effect on the renal (serum 
creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase (ALT), aspartate aminotransferase 
(AST), bilirubin).  In Phase 2 studies, there was a 
mild decrease of platelet count associated with 
ISIS 304801 administration that recovered in the 
post-treatment period and was not associated with 
platelet-related adverse events.  In the blinded 
ongoing clinical trials of ISIS 304801, 2 patients of 
142 dosed (as of February 29, 2016) had a 
decrease in platelet count to less than 50,000/mm3 
in the absence of major bleeding or clinically-
relevant non-major bleeding and had Study Drug 
paused as per the monitoring and stopping rules for 
platelet counts (Section 8.6.3).  Platelet counts 
recovered following suspension of dosing. 
To modify the clinical 
experience safety language 
to reflect updated blinded 
safety data from ongoing 
studies 
Section 3.6 Data and 
Safety Monitoring Board 
Independent added before Data and Safety 
Monitoring Board (DSMB) 
To clarify that the DSMB is 
independent  
Protocol Synopsis 
Study Population 
Section 5.1 Inclusion 
Criteria 
Section 6.3.1 
Contraception 
Requirements 
Abstinence is only acceptable as true abstinence, 
i.e., when this is in line with the preferred and usual
lifestyle of the patient.  Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, post-ovulation
methods), declaration of abstinence for the duration
of a trial and withdrawal are not acceptable methods
of contraception
Per the MHRA’s guidance to 
state that only true 
abstinence would be 
acceptable, and that periodic 
abstinence is not an 
acceptable method of 
contraception 
Section 6.2.10 Lipoprotein 
Lipase Activity Sample 
Collection 
Appendix A Schedule 
of Procedures 
Lipoprotein lipase (LPL) activity will be measured in 
ISIS 304801-CS16 rollover patients if needed for 
study qualification.  In brief, fasted patients will be 
given a low intravenous dose of heparin.  A blood 
sample will be drawn prior to and at 10 or 
15 minutes after the heparin administration for 
measurement of LPL activity as per instructions 
provided to the Investigator. 
Post heparin lipoprotein lipase activity can be 
conducted for study qualification (ISIS 304801-CS16 
rollover patients; please refer to Section 6.2.10) 
Lipoprotein lipase activity 
added as a qualification 
assessment for 
ISIS 304801-CS16 rollover 
patients 


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Protocol Section 
Description of Change 
Rationale 
Appendix A Schedule 
of Procedures 
Genetic testing can be conducted for study 
qualification (ISIS 304801-CS16 rollover patients); 
genetic testing will only be conducted if allowed in 
the geographic region and only after the patient has 
given specific written informed consent for genetic 
testing 
Genetic testing added as a 
qualification assessment for 
ISIS 304801-CS16 rollover 
patients 
Appendix A Schedule 
of Procedures 
Pregnancy testing was added at Weeks 4, 19, 32, 
44, and 58 
To reduce the time period 
between pregnancy tests  
Appendix A Schedule 
of Procedures 
Hematology blood draws were added at Weeks 12, 
16, 22, 25, 29, 35, 41, 47, and 51  
To implement more frequent 
evaluation of platelet counts 
to assess platelet 
fluctuations during the 
course of the study and to 
increase monitoring of 
platelet counts in patients for 
safety purposes 
Section 6.1.2 Treatment 
Period 
Appendix A Schedule 
of Procedures 
Blood sampling at Weeks 4, 8, 12, 16, 19, 22, 25, 
29, 32, 35, 41, 44, 47, 51, and 58  may be 
conducted by a home healthcare nurse 
To decrease study burden 
on the patient by removing 
the requirement for a visit to 
the clinic or study center for 
blood draws 
Section 6.1.3 
Pharmacokinetic (PK) 
Subgroup 
Appendix A Schedule 
of Procedures 
Patients in this subgroup will have an additional visit 
to the clinic, or by a home healthcare nurse, on 
Day 2 to collect a 24-hour post-dose blood draw 
after dosing on Day 1 
To decrease study burden 
on the patient by removing 
the requirement for a visit to 
the clinic or study center for 
the 24-hour PK blood draw  
Appendix A Schedule 
of Procedures 
Each time a hematology lab is drawn and sent to the 
central laboratory for analysis an additional sample 
should be collected in parallel and analyzed locally.  
In the event that both the central and local sample 
are uninterpretable (e.g., due to hemolyzed or 
clumped blood samples) another sample must be 
repeated within 1-week. 
To reduce the occurrence of 
unreportable hematology 
results (e.g., hemolyzed or 
clumped blood samples) 
Section 6.3.2 Treatment 
Period 
Appendix A Schedule 
of Procedures 
Wording was added to note that fasting should 
preferably not be more than 12 hours 
To provide guidance on the 
length of fasting  
Section 8.5.2 
Safety Monitoring for 
Platelet Count Results 
Addition to platelet monitoring rules that more 
frequent testing may also be required 
To allow more frequent 
monitoring of platelets when 
appropriate 
Section 8.5.6 
Safety Monitoring for 
Insulin, Oral Antidiabetic 
Medication and Glucose 
In addition, patients who are not on insulin (e.g., 
patients with type 2 diabetes), but use a glucometer 
should also bring their glucometer and/or 
glucometer log printout to every clinic visit. 
To implement that all 
patients, including those not 
on insulin, who use a 
glucometer should also bring 
their glucometer and/or 
glucometer log printout to 
every clinic visit 
Section 9.2 Regulatory 
Requirements 
In addition to the Investigator’s assessment of 
relatedness, the Sponsor or designee will evaluate 
the available information and perform an 
independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is 
not permissible to downgrade the Investigator’s 
opinion for the purposes of determining whether the 
SAE meets the definition of a SUSAR. 
To clarify guidance on 
determining relatedness of a 
SUSAR 


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PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome 
Study Objectives 
To evaluate the safety and efficacy of extended dosing with volanesorsen 
(volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center, open-label extension study of ISIS 304801-CS6 and 
ISIS 304801-CS16.  All patients will receive volanesorsen 300 mg once per 
week for 52 weeks.  Dietary counseling will be reinforced at intervals 
throughout the treatment and follow-up period.  Following the Week 52 visit, 
patients will enter a 13-week post-treatment evaluation period. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1.
Must give written informed consent to participate in the study (signed
and dated) and any authorizations required by law
2.
Age ≥ 18 years at time of informed consent
3.
Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16
(index studies) with an acceptable safety profile, per Sponsor and
Investigator judgement.  Patients who are enrolled in ISIS 304801-CS16
must also meet the following criteria in order to enter into the Extension
Study:
a.
History of chylomicronemia as evidenced by documentation of
lactescent serum (a creamy top layer after ultracentrifugation of a
fasting blood sample) or documentation of fasting TG measurement
≥ 880 mg/dL (10 mmol/L)
b.
A diagnosis of Familial Chylomicronemia Syndrome (Type 1
Hyperlipoproteinemia) by documentation of at least 1 of the
following:
•
Confirmed homozygote, compound heterozygote or double
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoC-II, GPIHBP1, or LMF1)
•
Post heparin plasma LPL activity of ≤ 20% of normal
c.
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the
ISIS 304801-CS16 study
4.
Able and willing to participate in a 65-week study
5.
Satisfy 1 of the following:
a.
Females:  Non-pregnant and non-lactating; surgically sterile (e.g.,
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral
oophorectomy), post-menopausal (defined as 12 months of
spontaneous amenorrhea in females > 55 years of age or, in
females ≤ 55 years, 12 months of spontaneous amenorrhea without
an alternative medical cause and FSH levels in the postmenopausal
range for the laboratory involved), abstinent*, or if engaged in
sexual relations of child-bearing potential, patient is using an
acceptable contraceptive method (refer to Section 6.3.1) from time
of signing the informed consent form until 13 weeks after the last
dose of Study Drug administration


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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
b. 
Males:  Surgically sterile, abstinent* or if engaged in sexual 
relations with a female of child-bearing potential, patient is utilizing 
an acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until 13 weeks after 
the last dose of Study Drug administration 
* Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Exclusion Criteria: 
1. 
Have any new condition or worsening of existing condition which in 
the opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. 
Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6- and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies which included a subset of patients with FCS.  This is an 
extension to the ISIS 304801-CS6 and ISIS 304801-CS16 index studies.  
Only the subset of patients from ISIS 304801-CS16 with FCS diagnosis may 
enter the Extension Study.  (Please refer to inclusion criteria #3, above) 
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A.  A 52-week 
treatment period during which volanesorsen will be administered as 
a once weekly SC injection 
• 
A 13-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the extension study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter the 13-week post-treatment 
evaluation period. 


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PROTOCOL SYNOPSIS Continued 
Safety and Tolerability Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis 
and MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during 
the treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an extension study to 
the double-blind placebo controlled ISIS 304801-CS6 and ISIS 304801-CS16 
index studies. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
QUALIFICATION 
PERIOD 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
Weeks 1 to 52 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
Weeks 53 to 65 
Safety, efficacy, PK and PD assessments 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OLE 
Open Label Extension 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of extended dosing with 
volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, 1 hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed to 
pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an open 
label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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In the completed studies there have been no volanesorsen associated laboratory abnormalities 
suggestive of an effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).  In Phase 2 studies, there 
was a mild decrease of platelet count associated with volanesorsen administration that recovered 
in the post-treatment period and was not associated with platelet-related adverse events (AEs).  
In the blinded ongoing clinical trials of ISIS 304801, 2 patients of 142 dosed (as of February 29, 
2016) had a decrease in platelet count to less than 50,000/mm3 in the absence of major bleeding 
or clinically-relevant non-major bleeding and had Study Drug paused as per the monitoring and 
stopping rules for platelet counts (Section 8.6.3).  Platelet counts recovered following suspension 
of dosing. 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label extension to the Phase 3 study of volanesorsen in patients with FCS 
(ISIS 304801-CS6 or ISIS 304801-CS16).  Up to approximately 70 patients will receive 300 mg 
once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
• A qualification period of up to 2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A. 
• A 52-week treatment period during which volanesorsen will be administered as a once 
weekly SC injection 
• A 13-week post-treatment evaluation period 
Please refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Qualification 
A period of up to 2 weeks is given to complete qualification assessments outlined in the 
Schedule of Procedures (Appendix A). 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule or Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 2 Study Center visits on 
Weeks 58 and 65. 
3.5 
End of Study 
The End-of-Study is last patient, last visit. 


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3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review (as needed) safety, 
tolerability and efficacy data collected on volanesorsen during this study.  Based on its ongoing 
assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review and meeting schedules are outlined in the 
DSMB Charter and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open label study are performed.  During the 
qualification period, the eligibility of the patient to continue in the extension study will be 
determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may be 
used for qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient 
identification number will be used to identify the patient throughout the extension trial and must 
be used on all study documentation related to that patient.  The patient identification number 
must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled after all qualification assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No patient 
may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index studies) with 
an acceptable safety profile, per Sponsor and Investigator judgement.  Patients who are 


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enrolled in ISIS 304801-CS16 must also meet the following criteria in order to enter into 
the Extension Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or documentation 
of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of at least 1 of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoC-II, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤ 20% of normal 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 study. 
4. Able and willing to participate in a 65-week study 
5. Satisfy 1 of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent*, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent* or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a 
trial and withdrawal are not acceptable methods of contraception 
5.2 
Exclusion Criteria 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 


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6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the extension study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
5 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling at Weeks 4, 8, 
12, 16, 19, 22, 25, 29, 32, 35, 41, 44, 47, 51, and 58 may be conducted by a home healthcare 
nurse .  Approval for study procedures to be conducted by a home healthcare nurse on other 
outpatient visit days will require prior approval by the Sponsor.  Patients must be fasted prior to 
drawing all blood samples and samples drawn locally must be sent to the central laboratory for 
analysis.  Every effort should be made to ensure the previous week’s dose is given 7 days prior 
to a scheduled clinic visit.  Dosing instructions and training will be provided to the patient where 
applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.3 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic, or by a home healthcare nurse, on Day 2 to 
collect a 24-hour post-dose blood draw after dosing on Day 1.  The detailed PK sampling 
schedules are outlined in Appendix C. 


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Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.4 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the 13-week 
post-treatment evaluation period.  This period consists of 2 Study Center visits on Weeks 58 and 
65 as outlined in the Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study. 
A list of these analytes is contained in Appendix B. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug (for ISIS 304801-CS16 rollover patients) and repeated at Week 52.  
Images will be evaluated by an independent assessor, blinded to the patient’s treatment 
assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 


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6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 1, 
Week 13, Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary  
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.2.10 
Lipoprotein Lipase Activity Sample Collection 
Lipoprotein lipase (LPL) activity will be measured in ISIS 304801-CS16 rollover patients if 
needed for study qualification.  In brief, fasted patients will be given a low intravenous dose of 
heparin.  A blood sample will be drawn prior to and at 10 or 15 minutes after the heparin 
administration for measurement of LPL activity as per instructions provided to the Investigator. 


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6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent* or, if engaged in sexual relations of child-bearing potential, practice effective 
contraception from the time of signing the informed consent form until at least 13 weeks after 
their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using one or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
*Note: A female condom and a male condom should not be used together as friction between the 
two can result in either product failing. 


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* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 


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8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
injection once weekly for Weeks 1-52. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 


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In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
below (refer to Sections 8.6.1 to 8.6.3) are met, the patient will be permanently discontinued 
from further treatment with volanesorsen, evaluated fully as outlined below and in consultation 
with the Sponsor Medical Monitor or appropriately qualified designee, and will be followed up 
in accordance with Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 


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Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring for Platelet Count Results 
In the event of any significant fall in platelet count, or if the absolute platelet count is 
75,000/mm3 or less, then the patient’s platelet counts should be monitored more frequently.  The 
frequency of monitoring and additional lab tests will be determined by the Sponsor Medical 
Monitor or designee in consultation with the Investigator.  
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin (e.g., patients with type 2 diabetes), but use a 
glucometer should also bring their glucometer and/or glucometer log printout to every clinic 
visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 


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All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L. 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as 1 in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 


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8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within 1 week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 


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8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
3 criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
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8.6.3 
Stopping Rules for Platelet Count Results 
In the event of a platelet count less than 50,000/mm3 that is associated with major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor. 
In the event of a platelet count less than 50,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered to 
≥ 100,000/mm3.  The suitability of the patient for continued dosing and the need for any 
modification to treatment schedule (refer to Section 8.7) will be determined by the Investigator 
in consultation with the Study Medical Monitor and will be based on factors such as the original 
rate of decline in the patient’s platelet count, whether any bleeding events were experienced by 
the patient, and the speed of recovery of platelet count upon holding of dosing. 
If after the first dosing re-challenge the platelet count again falls below 50,000/mm3, then dosing 
of the patient must be held until the platelet count again returns to at least 100,000/mm3.  The 
suitability of the patient for continued dosing and the need for any further modification to 
treatment schedule or dose (refer to Section 8.7) will be re-examined by the Investigator in 
consultation with the Study Medical Monitor based on (at least) the factors mentioned above. 
If after the second re-challenge the platelet count falls below 50,000/mm3 and is subsequently 
confirmed (see Section 8.5), dosing with volanesorsen will be stopped permanently.  The 
follow-up schedule for any events meeting this stopping criterion will be determined by the 
Investigator in consultation with the Study Medical Monitor. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
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5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
8.7 
Adjustment of Dose Frequency 
Dose adjustments, including dose interruptions, and/or decreasing the dose frequency will be 
allowed for safety and tolerability.  Any proposed adjustment to treatment schedule must be 
discussed with, and approved by, the Study Medical Monitor prior to initiation.  Up to 
2  adjustments in the treatment schedule may be allowed for patients that are unable to tolerate 
the once weekly dose (for example if platelet counts fall below 50,000/mm3 as described in 
Section 8.6.3).  If the patient remains stable after adjustment, they may be cautiously returned to 
the original once weekly regimen after consultation with the Study Medical Monitor. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be strongly encouraged to 
attend applicable landmark visits at Weeks 12, 13, 25, 26, and 51, 52 (calculated based on the 
time elapsed since Day 1) to collect fasting lipid panels and conduct safety assessments in 
accordance with the schedule of procedures in Appendix A.  Any patient who discontinues 
treatment after Week 44 should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last dose of Study Drug, in 
addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 


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8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to undergo a final follow-up visit (Week 65, see Appendix A) prior 
to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 


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recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 


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E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Independent DSMB will be notified of any SAE 
as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 


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9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 


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within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen e.g., 
confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
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9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by 1 of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by 1 of the following: 


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• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 


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• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known  (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 


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Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are  
defined as the average of Week 51 (Day 351) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints  
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 


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10.2 
Sample Size 
No sample size calculations were performed as this is an extension study to the double-blind, 
placebo-controlled ISIS 304801-CS6 and ISIS 304801-CS16 studies.  Approximately 70 patients 
may be eligible to enroll into this study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least 1 dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least 1 dose of volanesorsen, and have 
at least 1 evaluable PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient:  ISIS 304801-CS6 or 
ISIS 304801-CS16 index study baseline and the baseline in this open label study, which is 
defined as the average of Day 1 pre-dose assessment and the last measurement prior to Day 1 
(e.g., qualification assessments or assessments from final visit of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline for safety will be the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the extension 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this OLE study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 


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will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 
All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
studies.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index studies. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index studies, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index studies. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index studies. 
These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index studies. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index studies.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 


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Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index studies for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group of the index studies. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification by their prior treatment in Study 
ISIS 304801-CS6 and ISIS 304801-CS16 and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open label extension 
(OLE) study from the intensive PK subgroup, following a single dose (i.e., single-dose PK) or 
multiple doses (i.e., steady-state PK), depending on their earlier treatment in the index studies.  
On Week 1 Day 1 of the OLE study, patients who received placebo in the index study will 
receive the first treatment of volanesorsen (single-dose PK), while patients who received 
volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these 
patients reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time 
taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under 
the plasma concentration-time curve from time zero to 24 hours (AUC0-24hr) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration 
(CL0-24hr /F0-24hr) will be calculated from CL0-24hr /F0-24hr = Actual Dose/AUC0-24hr.  Mean 
residence time (MRT) from time zero to 24 hours after the SC administration will be calculated 
from the equation, MRT0-24hr = AUMC0-24hr /AUC0-24hr, where AUMC0-24hr is the area under the 
moment plasma concentration-time curve from time zero to 24 hours after the SC administration.  
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 


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10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 and study day.  
Subject ADA status (positive/negative or not evaluable) for all evaluable patients, along with the 
study day associated with the first positive IM status emerged (Tfirst, i.e., onset of ADA 
development), the last positive IM status observed (Tlast), the duration of ADA response (number 
of days between Tfirst and Tlast) if appropriate, the last ADA sample collection day, and subject - 
peak titer if applicable, will be listed by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16  study day.  Subjects with positive anti-volanesorsen antibody status may be 
further classified (when applicable) as being either ‘persistent’, ‘transient’, or ‘not determinable’, 
if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16.  Furthermore, onset, duration, and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
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11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 


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No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 


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13. 
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Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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CONFIDENTIAL 
Amendment 2 
Protocol 
22 April 2016 
 
58 
Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 2 
Protocol 
22 April 2016 
 
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14. 
APPENDICES 
 
 
 


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22 April 2016 
 
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Appendix A 
Schedule of Procedures 
 
 


ISIS 304801-CS7 
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Appendix A Schedule of Procedures 
Study Period 
Qual
a 
Treatment Period 
Post 
Treatment 
Follow-up
Study Week 
-2 to -1
Wk 
1 
Wk
4 
Wk
8 
Month 3 
Wk 
16 
Wk 
19 
Wk 
22 
Month 6 
Wk 
29 
Wk
32 
Wk 
35 
Wk
38 
Wk 
41 
Wk
44 
Wk 
47 
Month 12 
Wk
58 
Wk
65 
Wk
12 
Wk
13 
Wk
25 
Wk 
26 
Wk 
51 
Wk 52
or ET 
Study Day 
-14 to -7
1 
2 
22
50
78 
85 
106
127
148
169
176 
197 
218
239
260
281
302
323
351
358 
400
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
3 
3 
2 
2 
3 
3 
3 
3 
3 
3 
3 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X
k 
X
k
X
k
X
k 
X 
X
k 
X
k 
X
k 
X
k 
X 
X
k 
X
k 
X
k 
X 
X
k 
X
k 
X
k 
X
k 
X 
X
k 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight  
(+ height on Day 1 only) 
X 
X 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Physical Examination 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
l 
 
 
Echocardiography 
 
 
 
 
 
 
 
 
 
 
 
X
l 
 
 
 
 
 
 
 
 
X
l 
 
 
Blood Draw (Fasting)
c 
Chemistry Panel 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
CBC with Differential
b 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Lipid Panel 
X 
X 
 
X 
X 
X
 
X 
 
 
 
X
 
X 
 
 
 
X 
 
 
 
X
 
X 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
hsCRP, HbA1c, FPG, and de-lipidated 
free glycerol 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
X
m 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test
d 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Archived Serum & Plasma Samples
e 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 


ISIS 304801-CS7 
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22 April 2016
 
62 
Appendix A Schedule of Procedures Continued 
Study Period 
Qual
a 
Treatment Period 
Post 
Treatment 
Follow-up
Study Week 
-2 to -1
Wk 
1 
Wk
4 
Wk
8 
Month 3 
Wk 
16 
Wk 
19 
Wk 
22 
Month 6 
Wk 
29 
Wk 
32 
Wk 
35 
Wk 
38 
Wk 
41 
Wk 
44 
Wk 
47 
Month 12 
Wk
58 
Wk
65 
Wk
12 
Wk
13 
Wk
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7
1 
2 
22
50 
78 
85 
106
127
148
169
176 
197 
218
239
260
281
302
323
351
358 
400
449
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
3 
3 
2 
2 
3 
3 
3 
3 
3 
3 
3 
2 
2 
7 
7 
Urinalysis
c 
X 
X
n 
 
X 
X 
 
X
n 
 
X
n 
 
 
X
n 
 
X
n 
 
X
n 
 
X
n 
 
 
X
n 
X
n 
X
n 
Fundus Photography
f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
l 
 
 
Genetic testing for FCS diagnosis (if not 
available in medical history)
g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Postheparin Lipoprotein Lipase activity
h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Food/Drink Diary (quarterly)
i 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Diet/Alcohol Counseling
j 
X 
X 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Adverse Events
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Qualification procedures performed (Please refer to Section 4.1) 
b 
Each time a hematology lab is drawn and sent to the central laboratory for analysis an additional sample should be collected in parallel and analyzed locally. 
In the event that both the central and local sample are uninterpretable (e.g., due to hemolyzed or clumped blood samples) another sample must be repeated 
within 1-week 
c 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours.  During treatment period urine and blood 
samples will be collected prior to Study Drug administration.  Does not apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
f 
If possible, fundus photography should be completed prior to administration of the first dose of Study Drug (ISIS 304801-CS16 rollover patients) and repeated 
at Week 52 (Please refer to Section 6.2.2.2) 


ISIS 304801-CS7 
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22 April 2016
 
63 
Appendix A Schedule of Procedures Continued 
Legend Text Continued 
g 
Genetic testing can be conducted for study qualification (ISIS 304801-CS16 rollover patients); genetic testing will only be conducted if allowed in the 
geographic region and only after the patient has given specific written informed consent for genetic testing 
h 
Post-heparin lipoprotein lipase activity can be conducted for study qualification (ISIS 304801-CS16 rollover patients; please refer to Section 6.2.10) 
i 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
j 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
k 
Assessments and procedures to be conducted by either a home healthcare nurse, or the Study Center as arranged by the Study Center personnel 
l 
A ± 7-day window is allowed for MRI, echocardiography procedures and fundus photography 
m 
Full or abbreviated PK profile (see Appendix C) 
n 
Expanded urinalysis (see Appendix B) 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
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Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
65 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
66 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
67 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional. 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
68 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
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22 April 2016
 
69 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
Protocol 
 
22 April 2016
 
70 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL
Amendment 2
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71 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Supplement 1 - UK – 15 April 2016 
 
EudraCT No:  2015-003755-21 
 
 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
ISIS 304801-CS7 
Protocol Supplement I - UK 
15 A ril2016 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study ofVolanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Protocol Supplement 1 -UK -15 April2016 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 920
M.D., M.B.A. 
2 


ISIS 304801-CS7 
CONFIDENTIAL 
Protocol Supplement 1 - UK 
 
 
15 April 2016 
 
3 
Protocol Supplement Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome 
(FCS) 
Supplement: 
1 - UK 
Date:  
 
15 April 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol supplement 
for the protocol entitled “An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS)”, dated  
15 April 2016, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.  
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Protocol Supplement 1 - UK 
 
 
15 April 2016 
 
4 
PROTOCOL SUPPLEMENT - UK 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome 
(FCS) 
Supplement: 
1 - UK 
Date:  
 
15 April 2016 
 
The purpose of this supplement (to the global study protocol) is to fulfill MHRA requirements. 
The following changes will be made to the protocol: 
1. To indicate that the DSMB is independent. 
2. To revise the contraceptive requirements to state that abstinence is only acceptable as 
true abstinence, i.e., when it is in line with the preferred and usual lifestyle of the 
patient. 
3. To increase the frequency of the pregnancy testing. 
4. To clarify guidance on determining relatedness of a SUSAR. 
The following table provides a summary list of the modifications to the protocol. 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Protocol Supplement 1 - UK 
 
 
15 April 2016 
 
5 
LIST OF PROTOCOL MODIFICATIONS 
Section 
Modification 
Rationale 
Section 3.6  
Data and Safety 
Monitoring Board 
Was: 
The Data and Safety Monitoring Board (DSMB) will review (as 
needed) safety, tolerability and efficacy data collected on 
volanesorsen during this study.  Based on its ongoing assessment 
of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or 
continuing the study as planned.  Details on the safety 
assessments, frequency of review and meeting schedules are 
outlined in the DSMB Charter and/or the statistical analysis plan 
(SAP). 
 
Is: 
An independent Data and Safety Monitoring Board (DSMB) will be 
assembled to review safety, tolerability and efficacy (as needed) 
data collected on ISIS 304801 during this study.  Based on its 
ongoing assessment of the safety and tolerability of ISIS 304801, 
the DSMB will provide recommendations to the Sponsor for 
modifying, stopping or continuing the study as planned.  Details on 
the safety assessments, frequency of review, meeting schedules 
and controlled access to unblinded data are outlined in the DSMB 
Charter and/or the statistical analysis plan (SAP). 
To clarify that the 
DSMB is independent 
Section 5.1 
Inclusion Criteria 
 
Section 6.3.1 
Contraception 
Requirements 
New: 
* Abstinence is only acceptable as true abstinence, i.e., when this is 
in line with the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and 
withdrawal are not acceptable methods of contraception 
Per the MHRA’s 
guidance to state that 
only true abstinence 
would be acceptable, 
and that periodic 
abstinence is not an 
acceptable method of 
contraception 
Appendix A 
Schedule of 
Procedures 
Pregnancy testing added at Weeks 4, 19, 32, 44, and 58 
(See Appendix A below) 
To reduce the time 
period between 
pregnancy tests 
Section 9.2 
Regulatory 
Requirements 
Was: 
The Sponsor or designee will evaluate the available information 
and decide if there is a reasonable possibility that volanesorsen 
caused the AE and, therefore, meets the definition of a SUSAR. 
 
Is: 
In addition to the Investigator’s assessment of relatedness, the 
Sponsor or designee will evaluate the available information and 
perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an investigator’s decision it is not 
permissible to downgrade the investigator’s opinion for the 
purposes of determining whether the SAE meets the definition of a 
SUSAR. 
To clarify guidance on 
determining 
relatedness of a 
SUSAR 


ISIS 304801-CS7 
CONFIDENTIAL 
Protocol Supplement 1 - UK 
 
15 April 2016 
 
6 
Appendix A Schedule of Procedures 
Study Period 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3  
Wk 
19 
Month 6 
Wk 
32 
Wk 
38 
Wk 
44 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 
50 
78 
85 
127 169 176 
218 
260 
302 
351 
358 
400 
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
2 
2 
3 
3 
3 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
X 
Xh 
X 
Xh 
Xh 
X 
Xh 
X 
Xh 
Xh 
X 
Xh 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight (+ height on 
Day 1 only) 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Physical Examination 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
Echocardiography 
 
 
 
 
 
 
 
 
 
Xi 
 
 
 
 
Xi 
 
 
Fundus Photographyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
X 
X 
 
X 
Xh 
 
X 
Xh 
X 
Xh 
 
X 
Xh 
X 
CBC with Differential 
X 
X 
 
X 
X 
 
X 
Xh 
 
X 
Xh 
X 
Xh 
 
X 
Xh 
X 
Serum Lipid Panel 
X 
X 
 
X 
X 
Xh 
X 
 
Xh 
X 
 
X 
 
Xh 
X 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
hsCRP, HbA1c, FPG, and de-
lipidated free glycerol 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
Xk 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Archived Serum & Plasma 
Samplese 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
X 


ISIS 304801-CS7 
CONFIDENTIAL 
Protocol Supplement 1 - UK 
 
15 April 2016 
 
7 
Appendix A Schedule of Procedures Continued 
Study Period 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3 
Wk 
19 
Month 6 
Wk 
32 
Wk 
38 
Wk 
44 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 
50 
78 
85 
127 
169 176 
218 
260 
302 
351 
358 
400 
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
2 
2 
3 
3 
3 
2 
2 
7 
7 
Urinalysisc 
X 
Xj 
 
X 
X 
 
Xj 
Xj,h 
 
Xj 
Xj,h 
Xj 
Xj,h 
 
Xj 
Xj,h 
Xj 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Food/Drink Diary (quarterly)f 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Diet/Alcohol Counselingg 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Adverse Events 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Concomitant Medication 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
a 
Qualification procedures performed (Please refer to Section 4.1) 
b 
If possible, prior to administration of the first dose of Study Drug and repeated at Week 52 (Please refer to Section 6.2.2.2) 
c 
Blood samples to be collected after an overnight fast of at least 10 hours.  During treatment period urine and blood samples will be collected prior to Study 
Drug administration.  Does not apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
f 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
g 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
h 
To be collected by either a clinical service, or Study Center as arranged by the Study Center personnel.  Approval for study procedures to be conducted by a 
clinical service on other outpatient visit days will require prior approval by the Sponsor. 
i 
A ± 7 day window is allowed for MRI, echocardiography procedures and fundus photography 
j 
Expanded urinalysis (see Appendix B) 
k 
Full or abbreviated PK profile (see Appendix C) 


 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Protocol Amendment 1 –2 February 2016 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304801-CS7
Protocol
CONFIDENTIAL
Amendment I
2Februaw 2016
rsrs 304801-cs7
The APPROACH Open Label Bxtension Study
Volanesorsen (ISIS 304801)
An Open-Label Bxtension Study of Volanesorsen Administered
Subcutaneously to Patients with Familial Chylomicronemia
Syndrome (FCS)
Protocol Amendment 1 - 2 February 2016
Protocol History:
Original Protocol: 28 August 2015
Sponsor:
Ionis Pharmaceuticals, Inc.
2855 Gazelle Co
Carlsbad, CA
 M.D., M.B.A
2


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
3 
 
Ionis Protocol Number:  ISIS 304801-CS7 
Protocol Amendment 1 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone:
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
2 February 2016 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome 
(FCS) 
Amendment: 
Amendment 1 
Date:  
 
2 February 2016 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Extension Study of Volanesorsen Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS)”, dated 2 February 2016, and agree to conduct the 
study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT.......................................................................................................9 
PROTOCOL SYNOPSIS ............................................................................................................12 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................15 
STUDY GLOSSARY ...................................................................................................................16 
1. 
OBJECTIVES .....................................................................................................................18 
2. 
BACKGROUND AND RATIONALE ..............................................................................18 
2.1 
Overview of Disease ......................................................................................................18 
2.2 
Therapeutic Rationale ....................................................................................................19 
2.3 
Volanesorsen ..................................................................................................................20 
2.3.1 
Mechanism of Action .............................................................................................20 
2.3.2 
Chemistry ...............................................................................................................21 
2.3.3 
Preclinical Experience ............................................................................................22 
2.3.4 
Clinical Experience ................................................................................................23 
2.4 
Rationale for Dose and Schedule of Administration .....................................................24 
3. 
EXPERIMENTAL PLAN ..................................................................................................25 
3.1 
Study Design ..................................................................................................................25 
3.2 
Number of Study Centers ..............................................................................................25 
3.3 
Number of Patients ........................................................................................................25 
3.4 
Overall Study Duration and Follow-up .........................................................................25 
3.4.1 
Qualification ...........................................................................................................25 
3.4.2 
Treatment ................................................................................................................25 
3.4.3 
Post-Treatment .......................................................................................................25 
3.5 
End of Study ..................................................................................................................25 
3.6 
Data and Safety Monitoring Board ................................................................................26 
4. 
PATIENT ENROLLMENT ...............................................................................................26 
4.1 
Qualification ..................................................................................................................26 
4.2 
Enrollment .....................................................................................................................26 
5. 
PATIENT ELIGIBILITY ..................................................................................................26 
5.1 
Inclusion Criteria ...........................................................................................................26 
5.2 
Exclusion Criteria ..........................................................................................................27 
6. 
STUDY PROCEDURES ....................................................................................................27 
6.1 
Study Schedule ..............................................................................................................27 
6.1.1 
Qualification ...........................................................................................................28 
6.1.2 
Treatment Period ....................................................................................................28 
6.1.3 
Pharmacokinetic (PK) Subgroup ............................................................................28 
6.1.4 
Post-Treatment Period ............................................................................................29 
6.2 
Additional Study Assessments .......................................................................................29 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
6 
6.2.1 
Laboratory Assessments .........................................................................................29 
6.2.2 
Physical Exams and Vital Signs .............................................................................29 
6.2.2.1 
Eruptive Xanthoma ..........................................................................................29 
6.2.2.2 
Lipemia Retinalis .............................................................................................29 
6.2.3 
Echocardiography ...................................................................................................29 
6.2.4 
ECG ........................................................................................................................29 
6.2.5 
MRI ........................................................................................................................29 
6.2.6 
Quality of Life Assessments ...................................................................................30 
6.2.7 
Disease Symptom Diary .........................................................................................30 
6.2.8 
Diet Monitoring ......................................................................................................30 
6.2.9 
Family History ........................................................................................................30 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................30 
6.3.1 
Contraception Requirements ..................................................................................30 
6.3.2 
Other Requirements ................................................................................................31 
7. 
STUDY DRUG ....................................................................................................................31 
7.1 
Volanesorsen Description ..............................................................................................31 
7.2 
Packaging and Labeling .................................................................................................32 
7.3 
Study Drug Accountability ............................................................................................32 
8. 
TREATMENT OF PATIENTS .........................................................................................32 
8.1 
Volanesorsen Administration ........................................................................................32 
8.2 
Other Protocol-Required Drugs .....................................................................................32 
8.3 
Other Protocol-Required Treatment Procedures ............................................................32 
8.4 
Treatment Precautions ...................................................................................................33 
8.5 
Safety Monitoring Rules ................................................................................................33 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................33 
8.5.2 
Safety Monitoring Rules for Platelet Count Results ..............................................34 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................34 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................34 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................35 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........35 
8.5.7 
Safety Monitoring Rule for Documented Severe Hypoglycemia ..........................35 
8.5.8 
Safety Monitoring for Hyperglycemia ...................................................................36 
8.5.9 
Acute Pancreatitis ...................................................................................................37 
8.6 
Stopping Rules ...............................................................................................................37 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................37 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................38 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................38 
8.7 
Adjustment of Dose Frequency .....................................................................................39 
8.8 
Discontinuation of Study Treatment ..............................................................................39 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................40 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
7 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .40 
8.9 
Withdrawal of Patients from the Study ..........................................................................40 
8.10 
Concomitant Therapy and Procedures ...........................................................................41 
8.10.1 
Concomitant Therapy .............................................................................................41 
8.10.2 
Concomitant Procedures .........................................................................................41 
8.11 
Treatment Compliance ...................................................................................................41 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................42 
9.1 
Sponsor Review of Safety Information .........................................................................42 
9.2 
Regulatory Requirements ..............................................................................................42 
9.3 
Definitions .....................................................................................................................43 
9.3.1 
Adverse Event ........................................................................................................43 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................43 
9.3.3 
Serious Adverse Event (SAE) ................................................................................43 
9.4 
Monitoring and Recording Adverse Events ...................................................................44 
9.4.1 
Serious Adverse Events ..........................................................................................44 
9.4.2 
Non-Serious Adverse Events ..................................................................................44 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................44 
9.4.3.1 
Relationship to the Study Drug ........................................................................44 
9.4.3.2 
Severity ............................................................................................................45 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................45 
9.4.3.4 
Treatment Given for Adverse Event ................................................................45 
9.4.3.5 
Outcome of the Adverse Event ........................................................................45 
9.4.4 
Adjudication Committees .......................................................................................46 
9.5 
Procedures for Handling Special Situations ..................................................................46 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................46 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............47 
9.5.3 
Dosing Errors .........................................................................................................47 
9.5.4 
Contraception and Pregnancy .................................................................................47 
10. STATISTICAL CONSIDERATIONS ..............................................................................48 
10.1 
Study Endpoints .............................................................................................................48 
10.1.1 
Efficacy Endpoints .................................................................................................48 
10.1.2 
Safety Endpoints .....................................................................................................48 
10.2 
Sample Size ....................................................................................................................49 
10.3 
Populations .....................................................................................................................49 
10.4 
Definition of Baseline ....................................................................................................49 
10.5 
Interim Analysis .............................................................................................................50 
10.6 
Planned Methods of Analysis ........................................................................................50 
10.6.1 
Demographic and Baseline Characteristics ............................................................50 
10.6.2 
Safety Analysis .......................................................................................................50 
10.6.3 
Efficacy Analysis ...................................................................................................51 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
8 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................51 
10.6.4.1 
Pharmacokinetic Analysis ................................................................................51 
10.6.4.2 
Immunogenicity Analysis ................................................................................52 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................52 
11.1 
Informed Consent ..........................................................................................................52 
11.2 
Ethical Conduct of the Study .........................................................................................53 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................53 
11.4 
Patient Confidentiality ...................................................................................................53 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................54 
12.1 
Protocol Amendments ....................................................................................................54 
12.2 
Study Termination .........................................................................................................54 
12.3 
Study Documentation and Storage ................................................................................54 
12.4 
Study Monitoring ...........................................................................................................55 
12.5 
Language ........................................................................................................................56 
12.6 
Compensation for Injury ................................................................................................56 
13. REFERENCES ....................................................................................................................57 
14. APPENDICES .....................................................................................................................59 
Appendix A 
Schedule of Procedures ....................................................................................60 
Appendix B 
List of Laboratory Analytes .............................................................................63 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................65 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......67 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics ........................................................ 32 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence .................................................................................. 42 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 19 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides   
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 21 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 23 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
Amendment Number: 
1 
Amendment Date: 
2 February 2016 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 304801-CS7 dated 28 August 2015: 
1. To update the approximate anticipated number of patients that may enroll into the study 
(now approximately 70 patients) so that the number of patients is reflective of the 
estimated number of qualified patients from the ISIS 304801-CS6 and ISIS 304801-CS16 
index studies. 
2. To define the specific patient population from ISIS 304801-CS16 who will be allowed to 
enter the Open Label Extension Study. 
3. Clarification of when final assessments from the ISIS 304801-CS6 and ISIS 304801-
CS16 index studies may be used for enrollment into ISIS 304801-CS7. 
4. Clarification of how food and alcohol will be monitored during the study. 
5. An addition to the platelet monitoring rule language to allow for more frequent 
monitoring has been included. 
6. To provide guidance to Investigators with enrolled FCS patients who also have T2DM.  
Specific glucose monitoring rules are provided for patients on insulin and oral 
antidiabetic medications.  The definition of documented severe hypoglycemia is included 
and safety monitoring rules have been defined.  Also, specific monitoring rules are 
incorporated into the protocol for hyperglycemic events. 
Minor administrative changes or corrections (not included in the list of changes below) have 
been made throughout the protocol in order to improve the overall clarity of the protocol but 
these changes do not impact the study design. 
The following table provides a summary list of changes to the protocol: 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
10 
Protocol Section 
Description of Change 
Rationale 
Synopsis 
Section 3: 
Experimental Plan 
Section 10.2: 
Sample Size 
Up to approximately 50 patients dosed has been 
changed to up to approximately 70 patients 
dosed. 
Reflective of the updated patient 
numbers in the ISIS 304801-CS6 
study and the addition of ISIS 304801-
CS16 patients - with a diagnosis of 
FCS who will be allowed to enter the 
Extension Study after successful 
completion of ISIS 304801-CS16. 
Synopsis 
Study Population: 
Inclusion Criteria #3 
Section 5.1: Inclusion 
Criteria #3 
3.
Satisfactory completion of ISIS 304801-
CS6 or ISIS 304801-CS16 (index studies)
with an acceptable safety profile, per
Sponsor and Investigator judgement.
Patients who are enrolled in ISIS 304801-
CS16 must also meet the following criteria
in order to enter into the Extension Study:
a.
History of chylomicronemia as
evidenced by documentation of
lactescent serum (a creamy top layer
after ultracentrifugation of a fasting
blood sample) or documentation of
fasting TG measurement ≥ 880 mg/dL
(10 mmol/L)
b.
A diagnosis of Familial
Chylomicronemia Syndrome (Type 1
Hyperlipoproteinemia) by
documentation of at least one (1) of the
following:
•
Confirmed homozygote,
compound heterozygote or double
heterozygote for known loss-of-
function mutations in Type 1-
causing genes (such as LPL,
apoCII, GPIHBP1, or LMF1)
•
Post heparin plasma LPL activity
of ≤ 20% of normal
c.
Fasting TG ≥ 750 mg/dL (8.4 mmol/L)
at Screening for the ISIS 304801-CS16
study
Inclusion of the specific criteria that 
must be met in order for patients who 
successfully complete ISIS 304801-
CS16 to enter into the Open Label 
Extension Study. 
Section 4.1: 
Qualification 
Eligibility requirements provided for enrollment 
into the extension study. 
Clarification of when final assessments 
from the ISIS 304801-CS6 or 
ISIS 304801-CS16 study may be used 
for qualification. 
Section 6.1.1 
Qualification 
Appendix A 
Please refer to Section 4.1 and Appendix A. 
Deletion of repetitive information in 
Section 6.1.1 of when final 
assessments from ISIS 304801-CS6 
or ISIS 304801-CS16 can be used for 
qualification.  Qualification 
assessments explained in Section 4.1 
Section 6.1.2 
Study Procedures 
Approval for study procedures to be conducted 
by a clinical service on other outpatient visit 
days will require prior approval by the Sponsor. 
Blood sampling for lipid panels at 
Weeks 12, 25, and 51 may be 
conducted by a clinical service if more 
convenient for the patient.  Patient 
must get prior approval from the 
Sponsor for study procedures to be 
conducted by a clinical service on 
days not listed above 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
11 
 
Protocol Section 
Description of Change 
Rationale 
Section 6.2.2.1 
Eruptive Xanthoma 
Section 6.2.2.2 
Lipemia Retinalis 
Section 10.1.1 
Efficacy Endpoints  
Inquiries into the number and duration of 
Eruptive Xanthoma by study staff will occur at 
each clinic visit. Fundus photography will be 
performed prior to Day 1 Study Drug 
administration and at Week 52 
Eruptive Xanthoma and Lipemia 
Retinalis included as efficacy 
endpoints to obtain additional clinical 
endpoint data.  
Section 6.2.8: 
Diet Monitoring 
Explanation of how food/alcohol will be 
monitored throughout the course of the study. 
Clarification of how and when 
food/alcohol will be monitored by the 
patient, dietician or qualified study 
personnel. 
Section 8.5.2: 
Safety Monitoring 
Rules for Platelet 
Count Results 
Addition to platelet monitoring rules that more 
frequent testing may be required. 
More frequent monitoring of platelets 
may be warranted if a patient is 
experiencing a significant decline in 
platelet count. 
Section 8.5.6 
Section 8.5.7 
Section 8.5.8 
Glucose Monitoring 
in T2DM 
Addition of monitoring rules for patients with 
T2DM.  Monitoring rules established for patients 
on insulin and oral antidiabetic medications.  
Also included are monitoring rules for 
documented hypoglycemia and hyperglycemia. 
Added sections to enhance safety 
monitoring for 52-week study in 
diabetic patients with FCS. 
Appendix A 
Footnote “j” 
A ±7 day window is allowed for MRI and 
echocardiography 
Window expanded from 2 days to 7 
days for scheduling flexibility and 
patient convenience. 


ISIS 304801-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
12 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of extended dosing with volanesorsen 
(volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center, open-label extension study of ISIS 304801-CS6 and 
ISIS 304801-CS16.  All patients will receive volanesorsen 300 mg once per 
week for 52 weeks.  Dietary counseling will be reinforced at intervals 
throughout the treatment and follow-up period.  Following the Week 52 visit, 
patients will enter a 13 week post-treatment evaluation period. 
Number of Patients 
Up to approximately 70 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed and 
dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index 
studies) with an acceptable safety profile, per Sponsor and Investigator 
judgement.  Patients who are enrolled in ISIS 304801-CS16 must also 
meet the following criteria in order to enter into the Extension Study: 
a. 
History of chylomicronemia as evidenced by documentation of 
lactescent serum (a creamy top layer after ultracentrifugation of a 
fasting blood sample) or documentation of fasting TG measurement 
≥ 880 mg/dL (10 mmol/L) 
b. 
A diagnosis of Familial Chylomicronemia Syndrome (Type 1 
Hyperlipoproteinemia) by documentation of at least one (1) of the 
following: 
• 
Confirmed homozygote, compound heterozygote or double 
heterozygote for known loss-of-function mutations in Type 1-
causing genes (such as LPL, apoCII, GPIHBP1, or LMF1) 
• 
Post heparin plasma LPL activity of ≤ 20% of normal 
c. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the 
ISIS 304801-CS16 study 
4. 
Able and willing to participate in a 65-week study 
5. 
Satisfy one (1) of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent, or if engaged in sexual 
relations of child-bearing potential, patient is using an acceptable 
contraceptive method (refer to Section 6.3.1) from time of signing 
the informed consent form until 13 weeks after the last dose of 
Study Drug administration 


ISIS 304801-CS7 
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PROTOCOL SYNOPSIS Continued 
Study Population Continued 
Inclusion Criteria: Continued 
b. Males:  Surgically sterile, abstinent or if engaged in sexual relations 
with a female of child-bearing potential, patient is utilizing an 
acceptable contraceptive method (refer to Section 6.3.1) from the 
time of signing the informed consent form until 13 weeks after the 
last dose of Study Drug administration 
Exclusion Criteria: 
• 
Have any new condition or worsening of existing condition which in 
the opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index studies (ISIS 304801-CS6- and 
ISIS 304801-CS16) based on the pharmacodynamic and safety analysis of 
the Phase 2 studies which included a subset of patients with FCS.  This is an 
extension to the ISIS 304801-CS6 and ISIS 304801-CS16 index studies.  
Only the subset of patients from ISIS 304801-CS16 with FCS diagnosis may 
enter the Extension Study.  (Please refer to inclusion criteria #3, above) 
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor).  Please refer to Section 4.1 and Appendix A.  A 52-week 
treatment period during which volanesorsen will be administered as 
a once weekly SC injection 
• 
A 13-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the extension study or 
until results from the database locks for the ISIS 304801-CS6 and 
ISIS 304801-CS16 index studies becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter the 13-week post-treatment 
evaluation period. 
 
 


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PROTOCOL SYNOPSIS Continued 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis and 
MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during the 
treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
• 
Other symptoms: eruptive xanthoma, lipemia retinalis 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an extension study to 
the double-blind placebo controlled ISIS 304801-CS6 and ISIS 304801-CS16 
index studies. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
QUALIFICATION 
PERIOD 
 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
 
Weeks 1 to 52 
 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
 
Weeks 53 to 65 
 
2 clinic visits for safety, efficacy, PK and 
PD assessments 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Studies  
ISIS 304801-CS6 and ISIS 304801-CS16 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OLE 
Open Label Extension 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment-emergent 
occurring after first dose of Study Drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of extended dosing with 
volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/L probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, one (1) hypothesis is that large chylomicrons lodged in pancreatic capillaries are 
exposed to pancreatic lipase, with the subsequent release of free fatty acids through the 
hydrolysis of chylomicron-associated TGs.  High concentrations of free fatty acids are thought to 
damage pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 
2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 


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apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 
(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL (Brown et al. 
2010).  In addition, increased apoC-III content adversely affects apoE-mediated hepatic uptake 
of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated 
with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in the 
accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H1 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, 3 patients with FCS were treated with 300 mg/wk volanesorsen in an open 
label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
3 patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 
 
In clinical studies conducted to date volanesorsen has been well-tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 


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To date, there have been no volanesorsen associated laboratory abnormalities suggestive of an 
effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], bilirubin) despite many patients in the Phase 2 clinical 
trials receiving concomitant medications that are known to be associated with elevations in 
hepatic enzymes, such as fibrates and statins.  In Phase 2 studies, there was a mild decrease of 
platelet count associated with volanesorsen administration that recovered in the post-treatment 
period and was not associated with platelet-related adverse events (AEs). 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well-tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label extension to the Phase 3 study of volanesorsen in patients with FCS 
(ISIS 304801-CS6 or ISIS 304801-CS16).  Up to approximately 70 patients will receive 300 mg 
once weekly volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 70 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
• A qualification period of up to 2 weeks (unless approved by the Sponsor).  Please refer to 
Section 4.1 and Appendix A. 
• A 52-week treatment period during which volanesorsen will be administered as a once 
weekly SC injection 
• A 13-week post-treatment evaluation period 
Please refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Qualification 
A period of up to 2 weeks is given to complete qualification assessments outlined in the 
Schedule of Procedures (Appendix A). 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule or Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of 2 Study Center visits on 
Weeks 58 and 65. 
3.5 
End of Study 
The end of study is last patient, last visit. 


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3.6 
Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will review (as needed) safety, tolerability and 
efficacy data collected on volanesorsen during this study.  Based on its ongoing assessment of 
the safety and tolerability of volanesorsen, the DSMB will provide recommendations to the 
Sponsor for modifying, stopping or continuing the study as planned.  Details on the safety 
assessments, frequency of review and meeting schedules are outlined in the DSMB Charter 
and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification 
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Patients or their legally acceptable representatives must sign the consent form before any study-
specific procedures or evaluations related to this open label study are performed.  During the 
qualification period, the eligibility of the patient to continue in the extension study will be 
determined.  Final assessments from the ISIS 304801-CS6 or ISIS 304801-CS16 studies may be 
used for qualification.  A period of up to 2 weeks after completion of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  The patient 
identification number will be used to identify the patient throughout the extension trial and must 
be used on all study documentation related to that patient.  The patient identification number 
must remain constant throughout the extension trial. 
4.2 
Enrollment 
Patients will be enrolled after all qualification assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No patient 
may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Satisfactory completion of ISIS 304801-CS6 or ISIS 304801-CS16 (index studies) with 
an acceptable safety profile, per Sponsor and Investigator judgement.  Patients who are 


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enrolled in ISIS 304801-CS16 must also meet the following criteria in order to enter into 
the Extension Study: 
a. History of chylomicronemia as evidenced by documentation of lactescent serum (a 
creamy top layer after ultracentrifugation of a fasting blood sample) or 
documentation of fasting TG measurement ≥ 880 mg/dL (10 mmol/L) 
b. A diagnosis of Familial Chylomicronemia Syndrome (Type 1 Hyperlipoproteinemia) 
by documentation of at least one (1) of the following: 
• Confirmed homozygote, compound heterozygote or double heterozygote for 
known loss-of-function mutations in Type 1-causing genes (such as LPL, apoCII, 
GPIHBP1, or LMF1) 
• Post heparin plasma LPL activity of ≤ 20% of normal 
c. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening for the ISIS 304801-CS16 
study. 
4. Able and willing to participate in a 65-week study 
5. Satisfy one (1) of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
5.2 
Exclusion Criteria 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 


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6.1.1 
Qualification 
Please refer to Section 4.1 and Appendix A. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the extension study or until results from the database locks for 
the ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes 
first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
10 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 
concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling for lipid 
panels at Weeks 12, 25, and 51 may be conducted by a clinical service if more convenient for the 
patient.  Approval for study procedures to be conducted by a clinical service on other outpatient 
visit days will require prior approval by the Sponsor.  Patients must be fasted prior to drawing all 
blood samples and samples drawn locally must be sent to the central laboratory for analysis.  
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit.  Dosing instructions and training will be provided to the patient where 
applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  However, in the event that a visit does not occur or is delayed, all subsequent 
visits should be calculated based on the time elapsed since Day 1 rather than from the date of the 
previous visit. 
6.1.3 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic on Day 2 to collect a 24-hour post-dose blood 
draw after dosing on Day 1.  The detailed PK sampling schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 


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6.1.4 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the 13-week 
post-treatment evaluation period.  This period consists of 2 Study Center visits on Weeks 58 and 
65 as outlined in the Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study. 
A list of these analytes is contained in Appendix B. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.2.1 
Eruptive Xanthoma 
At each visit, patients will be asked whether they have had any episodes of eruptive xanthoma 
since their last visit and the number/duration of the events will be recorded.  Physical exams 
should also include skin examination for presence/resolution of eruptive xanthomas.  If a patient 
experiences an episode of eruptive xanthoma during the study, photos of the area should be 
taken, if possible. 
6.2.2.2 
Lipemia Retinalis 
If possible, lipemia retinalis will be assessed by fundus photography prior to administration of 
the first dose of Study Drug and repeated at Week 52.  Images will be evaluated by an 
independent assessor, blinded to the patient’s treatment assignment. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment-emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 


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MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 13, 
Week 26, Week 52, and Week 65. 
6.2.7 
Disease Symptom Diary  
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
The diets of patients enrolled in the study will be monitored as follows: 
1. All patients will be required to maintain a 7-day food diary prior to Week 1, Week 13, 
Week 26, Week 52, and Week 65. 
2. Patients will receive diet/alcohol counseling by qualified study personnel at clinic visits 
throughout the course of the study.  Qualified study personnel will telephone the patient 
to provide diet/alcohol counseling for visits that are conducted by a clinical service. 
3. In addition to the 7-day food diary and the diet /alcohol counseling during clinic visits, 
telephone calls from a dietitian or qualified study personnel to assess as to how each 
patient is maintaining their diet will be conducted randomly during the treatment and post 
treatment follow-up periods. 
6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
practice effective contraception from the time of signing the informed consent form until at least 
13 weeks after their last dose of study treatment. 
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet one (1) of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 


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For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the Study Drug. 
For female patients: 
• Using one (1) or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
*Note: A female condom and a male condom should not be used together as friction between 
the two can result in either product failing. 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours before visits requiring fasted blood 
sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 


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Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
injection once weekly for Weeks 1-52. 
Patients should receive one (1) dose per week, with weeks always defined relative to Study 
Day 1.  For example if a patient receives the first dose on a Monday, subsequent doses should be 
given on Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is 
not possible, the patient can reschedule the injection provided that 2 doses are administered at 
least 2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 


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8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from the final visits of ISIS 304801-CS6 and ISIS 304801-CS16 index studies if 
used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
below (refer to Sections 8.6.1 to 8.6.3) are met, the patient will be permanently discontinued 
from further treatment with volanesorsen, evaluated fully as outlined below and in consultation 
with the Sponsor Medical Monitor or appropriately qualified designee, and will be followed up 
in accordance with Section 8.8 of the protocol. 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 


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Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring Rules for Platelet Count Results 
If a patient’s platelet count falls by 30% or greater from baseline and the absolute platelet count 
is 75,000/mm3 or less, then the patient’s platelet counts should be monitored more frequently.  In 
the event of any significant fall in platelet count, the frequency of monitoring and additional lab 
tests will be determined by the Sponsor Medical Monitor or designee in consultation with the 
Investigator. 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically 
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 


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8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
Patients on insulin will monitor their glucose levels with a glucometer as per standard practice 
guidelines and bring their glucometer or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below. 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic therapy, 
as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode. 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit. 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the adverse event CRF. Documented symptomatic hypoglycemia is defined 
as typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L. 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF. 
8.5.7 
Safety Monitoring Rule for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as one (1) in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level 
≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 


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If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are certain 
classical signs and symptoms, of which patients should be aware as a clue that their blood glucose 
may be low.  Common symptoms include headache, heart pounding, confusion, disorientation, 
numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, anxiousness or 
nervousness, lightheadedness or dizziness, sweating, and weakness.  Many of these symptoms are 
listed in the diary provided to patients.  These diaries will be used only to assist the Investigator in 
assessing the event.  Appropriate source documentation should capture the necessary information on 
the event with the aid of the diaries.  Patients must be given adequate instructions on the use of the 
diaries. 
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it is 
safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, milk, 
or juice for example, then obtain and record a blood glucose value as soon as possible thereafter.  
The time and nature of treatment should be noted, and especially if any blood glucose result was 
before or after treatment.  It would be helpful for the patient to note if a contributory factor (e.g., 
missed or reduced meals, unaccustomed physical activity) occurred earlier in the day of the event. 
8.5.8 
Safety Monitoring for Hyperglycemia 
Upward dose titration and/or addition of any other anti-hyperglycemic agent(s) will not be 
allowed during the course of the study, unless specific threshold values are met at Week 13 or 
later and confirmed on subsequent testing (ideally within one (1) week of the initial test). 
HbA1c is monitored every 3 months throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer as per practice guidelines.  
If a fasting pre-breakfast SMPG value exceeds the specific glycemic limit, the patient should 
check it again on the following 2 days.  If all the fasting pre-breakfast values on 3 consecutive 
days exceed the specific limit, the patient should contact the Investigator and an unscheduled 
central laboratory FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 
• FPG > 270 mg/dL (15.0 mmol/L) 
• HbA1c > 9% (for patients with baseline HbA1c < 8% and HbA1c increase of more than 
1% from baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and in particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 


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• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event  
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
If none from the above-mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, additional medication may be introduced at the 
Investigator’s discretion and according to local guidelines after discussion with the Sponsor 
Medical Monitor. 
8.5.9 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with Study Drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
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8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
three criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24-hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24-hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rule for Platelet Count Results 
In the event of a platelet count less than 50,000/mm3 that is associated with major bleeding or 
clinically relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor. 
In the event of a platelet count less than 50,000/mm3, and in the absence of major bleeding or 
clinically relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered to 
≥ 100,000/mm3.  The suitability of the patient for continued dosing and the need for any 
modification to treatment schedule (refer to Section 8.7) will be determined by the Investigator 
in consultation with the Study Medical Monitor and will be based on factors such as the original 
rate of decline in the patient’s platelet count, whether any bleeding events were experienced by 
the patient, and the speed of recovery of platelet count upon holding of dosing. 
If after the first dosing re-challenge the platelet count again falls below 50,000/mm3, then dosing 
of the patient must be held until the platelet count again returns to at least 100,000/mm3.  The 
suitability of the patient for continued dosing and the need for any further modification to 
treatment schedule or dose (refer to Section 8.7) will be re-examined by the Investigator in 
consultation with the Study Medical Monitor based on (at least) the factors mentioned above. 
If after the second re-challenge the platelet count falls below 50,000/mm3 and is subsequently 
confirmed (see Section 8.5), dosing with volanesorsen will be stopped permanently.  The 
follow-up schedule for any events meeting this stopping criterion will be determined by the 
Investigator in consultation with the Study Medical Monitor. 


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Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
8.7 
Adjustment of Dose Frequency 
Dose adjustments, including dose interruptions, and/or decreasing the dose frequency will be 
allowed for safety and tolerability.  Any proposed adjustment to treatment schedule must be 
discussed with, and approved by, the Study Medical Monitor prior to initiation.  Up to 
2  adjustments in the treatment schedule may be allowed for patients that are unable to tolerate 
the once weekly dose (for example if platelet counts fall below 50,000/mm3 as described in 
Section 8.6.3).  If the patient remains stable after adjustment, they may be cautiously returned to 
the original once weekly regimen after consultation with the Study Medical Monitor. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 


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8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be strongly encouraged to 
attend applicable landmark visits at Weeks 12, 13, 25, 26, and 51, 52 (calculated based on the 
time elapsed since Day 1) to collect fasting lipid panels and conduct safety assessments in 
accordance with the schedule of procedures in Appendix A.  Any patient who discontinues 
treatment after Week 44 should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last dose of Study Drug, in 
addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to undergo a final follow-up visit (Week 65, see Appendix A) prior 
to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 


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8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), -glucagon-like peptide-1 (GLP-1) agonists, Glybera, 
or systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of 
existing oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, 
anticoagulants, or drugs or dietary supplements with potential lipid-altering effects should not be 
adjusted.  Study patients are prohibited from receiving other experimental agents during the 
study.  This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 


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9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Data and Safety Monitoring Board (DSMB) will 
be notified of any SAE as specified in the DSMB charter. 
The Sponsor or designee will evaluate the available information and decide if there is a 
reasonable possibility that volanesorsen caused the AE and, therefore, meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 


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9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 


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9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by one (1) of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen e.g., 
confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
 


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• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by one (1) of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by one (1) of the 
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• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is a SAE then the event’s outcome is characterized by one (1) of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 


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The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
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Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known  (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are  
defined as the average of Week 51 (Day 351) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III 
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
• Other symptoms: eruptive xanthoma, lipemia retinalis 
10.1.2 
Safety Endpoints  
• Adverse events including adjudicated events of pancreatitis and MACE 


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• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 
10.2 
Sample Size 
No sample size calculations were performed as this is an extension study to the double-blind, 
placebo-controlled ISIS 304801-CS6 and ISIS 304801-CS16 studies.  Approximately 70 patients 
may be eligible to enroll into this study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least one (1) dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least one (1) dose of volanesorsen, and 
have at least one (1) evaluable PK sample collected, analyzed, and reported. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, 2 baselines are defined for each patient:  ISIS 304801-CS6 or 
ISIS 304801-CS16 index study baseline and the baseline in this open label study, which is 
defined as the average of Day 1 pre-dose assessment and the last measurement prior to Day 1 
(e.g., qualification assessments or assessments from final visit of the ISIS 304801-CS6 or 
ISIS 304801-CS16 index studies if used for qualification). 
For other measurements, baseline for patients on active treatment in the ISIS 304801-CS6 or 
ISIS 304801-CS16 index study will be the ISIS 304801-CS6 or ISIS 304801-CS16 index study 
baseline.  For patients on placebo in the ISIS 304801-CS6 or ISIS 304801-CS16 index study, 
baseline for safety will be the last non-missing assessment prior to the first dose of Study Drug. 


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10.5 
Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the extension 
study or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are 
locked and unblinded.  Both safety and efficacy information from this OLE study may be 
summarized during this interim analysis.  Efficacy analyses will be detailed in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 
will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 
All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
studies.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index studies. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index studies.  Narratives of treatment-emergent 
deaths, serious and significant AEs, including early withdrawals due to AEs, will also be 
provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index studies, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index studies. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index studies. 


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These safety variables will also be presented as change and percent change from baseline over 
time after Study Drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index studies. 
10.6.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index studies.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index studies for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 
The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, quality of life assessments, and comparison of other symptoms including eruptive 
xanthomas and lipemia retinalis will be summarized by treatment group of the index studies. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
10.6.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification by their prior treatment in Study 
ISIS 304801-CS6 and ISIS 304801 CS16 and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open label extension 
(OLE) study from the intensive PK subgroup, following a single dose (i.e., single-dose PK) or 
multiple doses (i.e., steady-state PK), depending on their earlier treatment in the index studies.  
On Week 1 Day 1 of the OLE study, patients who received placebo in the index study will 
receive the first treatment of volanesorsen (single-dose PK), while patients who received 
volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these 
patients reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time 
taken to reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under 
the plasma concentration-time curve from time zero to 24 hours (AUC0-24hr) will be calculated 
using the linear trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration 
(CL0-24hr /F0-24hr) will be calculated from CL0-24hr /F0-24hr = Actual Dose/AUC0-24hr.  Mean 


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residence time (MRT) from time zero to 24 hours after the SC administration will be calculated 
from the equation, MRT0-24hr = AUMC0-24hr /AUC0-24hr, where AUMC0-24hr is the area under the 
moment plasma concentration-time curve from time zero to 24 hours after the SC administration.  
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and IM 
status.  Additional details regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.6.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with Study Drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in study ISIS 304801-CS6 or ISIS 304801-CS16 and study day.  
Subject ADA status (positive/negative or not evaluable) for all evaluable patients, along with the 
study day associated with the first positive IM status emerged (Tfirst, i.e., onset of ADA 
development), the last positive IM status observed (Tlast), the duration of ADA response (number 
of days between Tfirst and Tlast) if appropriate, the last ADA sample collection day, and subject - 
peak titer if applicable, will be listed by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16  study day.  Subjects with positive anti-volanesorsen antibody status may be 
further classified (when applicable) as being either ‘persistent’, ‘transient’, or ‘not determinable’, 
if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6 and 
ISIS 304801-CS16.  Furthermore, onset, duration, and titer of the ADA response, if applicable, 
will be summarized as median, quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase 2 and 3 studies and reported separately. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 


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Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 


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In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 


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• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor 
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 


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12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 


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13. 
REFERENCES 
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to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev. Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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Ito Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene expression in 
transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein 
containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 
239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, et al. Identification of mutations in the lipoprotein lipase (LPL) and 
apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). Clinica 
Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


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14. 
APPENDICES 
 


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Appendix A 
Schedule of Procedures 
 
 


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Appendix A Schedule of Procedures 
Study Period 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3  
Wk 
19 
Month 6 
Wk 
32 
Wk 
38 
Wk 
44 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 
50 
78 
85 
127 169 176 
218 
260 
302 
351 
358 
400 
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
2 
2 
3 
3 
3 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
X 
Xh 
X 
Xh 
Xh 
X 
Xh 
X 
Xh 
Xh 
X 
Xh 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight (+ height on 
Day 1 only) 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Physical Examination 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
Echocardiography 
 
 
 
 
 
 
 
 
 
Xi 
 
 
 
 
Xi 
 
 
Fundus Photographyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
Blood Draw (Fasting)c 
Chemistry Panel 
X 
X 
 
X 
X 
 
X 
Xh 
 
X 
Xh 
X 
Xh 
 
X 
Xh 
X 
CBC with Differential 
X 
X 
 
X 
X 
 
X 
Xh 
 
X 
Xh 
X 
Xh 
 
X 
Xh 
X 
Serum Lipid Panel 
X 
X 
 
X 
X 
Xh 
X 
 
Xh 
X 
 
X 
 
Xh 
X 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
hsCRP, HbA1c, FPG, and de-
lipidated free glycerol 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
Xk 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testd 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Archived Serum & Plasma 
Samplese 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
X 


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Appendix A Schedule of Procedures Continued 
Study Period 
 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3 
Wk 
19 
Month 6 
Wk 
32 
Wk 
38 
Wk 
44 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 
50 
78 
85 
127 
169 176 
218 
260 
302 
351 
358 
400 
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
2 
2 
3 
3 
3 
2 
2 
7 
7 
Urinalysisc 
X 
Xj 
 
X 
X 
 
Xj 
Xj,h 
 
Xj 
Xj,h 
Xj 
Xj,h 
 
Xj 
Xj,h 
Xj 
Weekly Study Drug:  SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Food/Drink Diary (quarterly)f 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Diet/Alcohol Counselingg 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Adverse Events 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Concomitant Medication 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
a 
Qualification procedures performed (Please refer to Section 4.1) 
b 
If possible, prior to administration of the first dose of Study Drug and repeated at Week 52 (Please refer to Section 6.2.2.2) 
c 
Blood samples to be collected after an overnight fast of at least 10 hours.  During treatment period urine and blood samples will be collected prior to Study 
Drug administration.  Does not apply to 24-hour PK blood draw 
d 
Females of childbearing potential only 
e 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
f 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
g 
To reinforce compliance to the diet and alcohol restrictions.  Random diet/alcohol assessments (phone visits) will also be performed by dietician or study 
personnel 
h 
To be collected by either a clinical service, or Study Center as arranged by the Study Center personnel.  Approval for study procedures to be conducted by a 
clinical service on other outpatient visit days will require prior approval by the Sponsor. 
i 
A ± 7 day window is allowed for MRI, echocardiography procedures and fundus photography 
j 
Expanded urinalysis (see Appendix B) 
k 
Full or abbreviated PK profile (see Appendix C) 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
63 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
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2 February 2016 
 
64 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
65 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
66 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional. 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
67 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
68 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
69 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


ISIS 304804-CS7 
CONFIDENTIAL 
Amendment 1 
Protocol 
2 February 2016 
 
70 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


 
 
Sponsor: 
Isis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator:
Akcea Therapeutics
55 Cambridge Parkway, Suite 100
Cambridge, MA 02142
 
 
ISIS 304801-CS7 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Original Protocol – 28 August 2015 
 
EudraCT No:  2015-003755-21 
 
 
 


ISIS 304801-CS7
Protocol
CONFIDENTIAL
Original
28 Ausust 2015
rsrs 304801-cs7
The APPROACH Open Label Extension Study
Volanesorsen (ISIS 304801)
An Open-Label Extension Study of Volanesorsen Administered
Subcutaneously to Patients with Familial Chylomicronemia
Syndrome (FCS)
Original Protocol - 28 August 2015
Sponsor:
Isis Pharmaceuticals, Inc
2855 Gazelle Court
Carlsbad, CA 92010
M.D., M.B.A.
2


ISIS 304801-CS7 
CONFIDENTIAL
Original
Protocol 
 
28 August 2015
 
3 
 
Isis Protocol Number:  ISIS 304801-CS7 
Original Protocol 
EudraCT No:  2015-003755-21 
Clinical Phase:  3 
 
The APPROACH Open Label Extension Study 
Volanesorsen (ISIS 304801) 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS) 
 
Trial Sponsor: 
Isis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
 
Key Sponsor Contact: 
 Ph.D. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Date: 
28 August 2015 
Confidentiality Statement 
This document contains confidential information of Isis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Isis Pharmaceuticals, Inc. 


ISIS 304801-CS7 
CONFIDENTIAL 
Original 
Protocol 
28 August 2015 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 304801-CS7 
Protocol Title: 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome 
(FCS) 
Date:  
 
28 August 2015 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open-Label Extension Study of Volanesorsen Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS)”, dated 28 August 2015, and agree to conduct the 
study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Isis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Original 
Protocol 
28 August 2015 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL SYNOPSIS ..............................................................................................................9 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................12 
STUDY GLOSSARY ...................................................................................................................13 
1. 
OBJECTIVES .....................................................................................................................15 
2. 
BACKGROUND AND RATIONALE ..............................................................................15 
2.1 
Overview of Disease ......................................................................................................15 
2.2 
Therapeutic Rationale ....................................................................................................16 
2.3 
Volanesorsen ..................................................................................................................17 
2.3.1 
Mechanism of Action .............................................................................................17 
2.3.2 
Chemistry ...............................................................................................................18 
2.3.3 
Preclinical Experience ............................................................................................19 
2.3.4 
Clinical Experience ................................................................................................20 
2.4 
Rationale for Dose and Schedule of Administration .....................................................21 
3. 
EXPERIMENTAL PLAN ..................................................................................................22 
3.1 
Study Design ..................................................................................................................22 
3.2 
Number of Study Centers ..............................................................................................22 
3.3 
Number of Patients ........................................................................................................22 
3.4 
Overall Study Duration and Follow-up .........................................................................22 
3.4.1 
Qualification ...........................................................................................................22 
3.4.2 
Treatment ................................................................................................................22 
3.4.3 
Post-Treatment .......................................................................................................22 
3.5 
End of Study ..................................................................................................................22 
3.6 
Data and Safety Monitoring Board ................................................................................22 
4. 
PATIENT ENROLLMENT ...............................................................................................23 
4.1 
Qualification ..................................................................................................................23 
4.2 
Enrollment .....................................................................................................................23 
5. 
PATIENT ELIGIBILITY ..................................................................................................23 
5.1 
Inclusion Criteria ...........................................................................................................23 
5.2 
Exclusion Criteria ..........................................................................................................24 
6. 
STUDY PROCEDURES ....................................................................................................24 
6.1 
Study Schedule ..............................................................................................................24 
6.1.1 
Qualification ...........................................................................................................24 
6.1.2 
Treatment Period ....................................................................................................24 
6.1.3 
Pharmacokinetic (PK) Subgroup ............................................................................25 
6.1.4 
Post-Treatment Period ............................................................................................25 
6.2 
Additional Study Assessments .......................................................................................25 
6.2.1 
Laboratory Assessments .........................................................................................25 


ISIS 304801-CS7 
CONFIDENTIAL 
Original 
Protocol 
28 August 2015 
 
6 
6.2.2 
Physical Exams and Vital Signs .............................................................................25 
6.2.3 
Echocardiography ...................................................................................................26 
6.2.4 
ECG ........................................................................................................................26 
6.2.5 
MRI ........................................................................................................................26 
6.2.6 
Quality of Life Assessments ...................................................................................26 
6.2.7 
Disease Symptom Diary .........................................................................................26 
6.2.8 
Diet Monitoring ......................................................................................................26 
6.2.9 
Family History ........................................................................................................26 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................26 
6.3.1 
Contraception Requirements ..................................................................................26 
6.3.2 
Other Requirements ................................................................................................27 
7. 
STUDY DRUG ....................................................................................................................28 
7.1 
Volanesorsen Description ..............................................................................................28 
7.2 
Packaging and Labeling .................................................................................................28 
7.3 
Study Drug Accountability ............................................................................................28 
8. 
TREATMENT OF PATIENTS .........................................................................................28 
8.1 
Volanesorsen Administration ........................................................................................28 
8.2 
Other Protocol-Required Drugs .....................................................................................29 
8.3 
Other Protocol-Required Treatment Procedures ............................................................29 
8.4 
Treatment Precautions ...................................................................................................29 
8.5 
Safety Monitoring Rules ................................................................................................29 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................30 
8.5.2 
Safety Monitoring Rules for Platelet Count Results ..............................................30 
8.5.3 
Safety Monitoring for Minor Bleeding Events .......................................................30 
8.5.4 
Safety Monitoring for Constitutional Symptoms ...................................................31 
8.5.5 
Safety Monitoring for LDL-C Elevations ..............................................................31 
8.5.6 
Acute Pancreatitis ...................................................................................................31 
8.6 
Stopping Rules ...............................................................................................................31 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................31 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................32 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................32 
8.7 
Adjustment of Dose Frequency .....................................................................................33 
8.8 
Discontinuation of Study Treatment ..............................................................................33 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period ...........................34 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period .34 
8.9 
Withdrawal of Patients from the Study ..........................................................................34 
8.10 
Concomitant Therapy and Procedures ...........................................................................35 
8.10.1 
Concomitant Therapy .............................................................................................35 
8.10.2 
Concomitant Procedures .........................................................................................35 
8.11 
Treatment Compliance ...................................................................................................35 


ISIS 304801-CS7 
CONFIDENTIAL 
Original 
Protocol 
28 August 2015 
 
7 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................36 
9.1 
Sponsor Review of Safety Information .........................................................................36 
9.2 
Regulatory Requirements ..............................................................................................36 
9.3 
Definitions .....................................................................................................................37 
9.3.1 
Adverse Event ........................................................................................................37 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................37 
9.3.3 
Serious Adverse Event (SAE) ................................................................................37 
9.4 
Monitoring and Recording Adverse Events ...................................................................38 
9.4.1 
Serious Adverse Events ..........................................................................................38 
9.4.2 
Non-Serious Adverse Events ..................................................................................38 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................38 
9.4.3.1 
Relationship to the Study Drug ........................................................................38 
9.4.3.2 
Severity ............................................................................................................39 
9.4.3.3 
Action Taken with Volanesorsen .....................................................................39 
9.4.3.4 
Treatment Given for Adverse Event ................................................................39 
9.4.3.5 
Outcome of the Adverse Event ........................................................................39 
9.4.4 
Adjudication Committees .......................................................................................40 
9.5 
Procedures for Handling Special Situations ..................................................................40 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................40 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............40 
9.5.3 
Dosing Errors .........................................................................................................41 
9.5.4 
Contraception and Pregnancy .................................................................................41 
10. STATISTICAL CONSIDERATIONS ..............................................................................42 
10.1 
Study Endpoints .............................................................................................................42 
10.1.1 
Efficacy Endpoints .................................................................................................42 
10.1.2 
Safety Endpoints .....................................................................................................42 
10.2 
Sample Size ....................................................................................................................43 
10.3 
Populations .....................................................................................................................43 
10.3 
Definition of Baseline ....................................................................................................43 
10.4 
Interim Analysis .............................................................................................................43 
10.5 
Planned Methods of Analysis ........................................................................................43 
10.5.1 
Demographic and Baseline Characteristics ............................................................44 
10.5.2 
Safety Analysis .......................................................................................................44 
10.5.3 
Efficacy Analysis ...................................................................................................44 
10.5.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................45 
10.5.4.1 
Pharmacokinetic Analysis ................................................................................45 
10.5.4.2 
Immunogenicity Analysis ................................................................................45 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................46 
11.1 
Informed Consent ..........................................................................................................46 
11.2 
Ethical Conduct of the Study .........................................................................................46 


ISIS 304801-CS7 
CONFIDENTIAL 
Original 
Protocol 
28 August 2015 
 
8 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................47 
11.4 
Patient Confidentiality ...................................................................................................47 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................47 
12.1 
Protocol Amendments ....................................................................................................47 
12.2 
Study Termination .........................................................................................................48 
12.3 
Study Documentation and Storage ................................................................................48 
12.4 
Study Monitoring ...........................................................................................................48 
12.5 
Language ........................................................................................................................49 
12.6 
Compensation for Injury ................................................................................................49 
13. REFERENCES ....................................................................................................................50 
14. APPENDICES .....................................................................................................................52 
Appendix A 
Schedule of Procedures ....................................................................................53 
Appendix B 
List of Laboratory Analytes .............................................................................56 
Appendix C 
Pharmacokinetic Sampling Schedule ...............................................................58 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......60 
 
 
TABLE OF TABLES 
Page 
Table 1 
Volanesorsen (ISIS 304801) Characteristics ........................................................ 28 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term 
and the Expected Incidence .................................................................................. 36 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms .............. 16 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides 
(MOE-Gapmer).  The sequence of volanesorsen is shown ................................... 18 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen .............. 20 
 
 


ISIS 304801-CS7 
CONFIDENTIAL 
Original 
Protocol 
28 August 2015 
 
9 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-Label Extension Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome  
Study Objectives 
To evaluate the safety and efficacy of extended dosing with volanesorsen 
(volanesorsen sodium 300 mg) in patients with FCS 
Study Design 
This is a multi-center, open-label extension study of ISIS 304801-CS6.  All 
patients will receive volanesorsen 300 mg once per week for 52 weeks.  
Dietary counseling will be reinforced at intervals throughout the treatment and 
follow-up period.  Following the Week 52 visit, patients will enter a 13 week 
post-treatment evaluation period. 
Number of Patients 
Up to approximately 50 patients dosed 
Study Population 
Inclusion Criteria: 
1. 
Must give written informed consent to participate in the study (signed and 
dated) and any authorizations required by law 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Satisfactory completion of ISIS 304801-CS6 (index study) with an 
acceptable safety profile, per Sponsor and Investigator judgment 
4. 
Able and willing to participate in a 65-week study 
5. 
Satisfy one of the following: 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), post-menopausal (defined as 12 months of 
spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved), abstinent, or if engaged in sexual 
relations of child-bearing potential, patient is using an acceptable 
contraceptive method (refer to Section 6.3.1) from time of signing 
the informed consent form until 13 weeks after the last dose of 
Study Drug administration 
b. 
Males:  Surgically sterile, abstinent or if engaged in sexual relations 
with a female of child-bearing potential, patient is utilizing an 
acceptable contraceptive method (refer to Section 6.3.1) from the 
time of signing the informed consent form until 13 weeks after the 
last dose of Study Drug administration 
Exclusion Criteria: 
1. 
Have any new condition or worsening of existing condition which in the 
opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study 
2. 
Unwilling to comply with lifestyle requirements for the duration of the 
study (Section 6.3) 
Treatment Group 
Volanesorsen 300 mg once per week  
Study Drug Administration 
Volanesorsen will be administered as subcutaneous (SC) injections. 


ISIS 304801-CS7 
CONFIDENTIAL 
Original 
Protocol 
28 August 2015 
 
10 
PROTOCOL SYNOPSIS Continued 
Dose Adjustments 
Dose adjustments, including dose interruptions and/or decreasing the dose 
frequency will be allowed for safety or tolerability after consultation with the 
Sponsor Medical Monitor. 
Rationale for Dose and Schedule 
Selection 
The dose of 300 mg once weekly was chosen for the double-blinded 
placebo-controlled Phase 3 index study (ISIS 304801-CS6) based on the 
pharmacodynamic and safety analysis of the Phase 2 studies which included 
a subset of patients with FCS.  This is an extension to the ISIS 304801-CS6 
study. 
Study Visit Schedule and 
Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
A qualification period of up to 2 weeks (unless approved by the 
Sponsor) 
• 
A 52-week treatment period during which volanesorsen will be 
administered as a once weekly SC injection 
• 
A 13-week post-treatment evaluation period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to 
lipid data through the last patient’s Week 13 visit of the extension study or 
until results from the database lock for the index study (ISIS 304801-CS6) 
becomes available, whichever comes first. 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events 
(AE), concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, immunogenicity (IM) testing, 
liver/spleen magnetic resonance imaging (MRI), ECGs, echocardiograms and 
quality of life assessments will be performed according to the schedule of 
procedures in Appendix A.  Dietary counseling will be repeated at intervals 
throughout the treatment and follow-up period and a daily food/drink diary will 
be completed for the week prior to each quarterly visit by each patient.  
Following the Week 52 visit, patients will enter the 13-week post-treatment 
evaluation period. 
Safety and Tolerability 
Evaluations 
Overall safety and tolerability of volanesorsen will be assessed by 
determining the incidence and severity of adverse and serious adverse 
events (including independently adjudicated events of acute pancreatitis and 
MACE), withdrawals due to adverse events, and changes in laboratory and 
other safety parameters. 
Planned Analyses 
Safety Endpoints: 
• 
Adverse events including adjudicated events of acute pancreatitis and 
MACE 
• 
Vital signs and weight 
• 
Physical examinations 
• 
Clinical  laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis) 
• 
Echocardiography 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
• 
MRIs 
 
 


ISIS 304801-CS7 
CONFIDENTIAL
Original
Protocol 
 
28 August 2015
 
11 
PROTOCOL SYNOPSIS Continued 
Planned Analyses Continued 
Efficacy Endpoints: 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Frequency and severity of patient reported abdominal pain during the 
treatment period 
• 
Percent change and change from baseline in other fasting lipid 
measurements including total cholesterol, non-high-density 
lipoprotein-cholesterol (non-HDL-C), apolipoprotein B [apoB], high-
density lipoprotein-cholesterol (HDL-C), apolipoprotein A-1 [apoA-1], 
very-low-density lipoprotein-cholesterol (VLDL-C), and LDL-C 
• 
Percent change from baseline in fasting total apolipoprotein C-III 
(apoC-III) 
• 
Quality of Life questionnaires (EQ-5D, SF-36) 
• 
Adjudicated acute pancreatitis event rate 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
volanesorsen as follows: trough levels (pre-dose) throughout treatment and 
post-treatment levels during the post-treatment follow-up period.  In a subset 
of patients, more frequent assessment of plasma concentrations of 
volanesorsen will be performed to determine volanesorsen pharmacokinetic 
parameters.  Plasma sample collection time points are detailed in Appendix A 
and Appendix C. 
Statistical Considerations 
No sample size calculations were performed as this is an extension study to 
the double-blind placebo controlled ISIS 304801-CS6 study. 
Sponsor 
Isis Pharmaceuticals, Inc. 
Collaborator 
Akcea Therapeutics 


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12 
STUDY DESIGN AND TREATMENT SCHEMA 
 
QUALIFICATION 
PERIOD 
 
Weeks -2 to -1 
EARLY 
TERMINATION 
(ET) 
 
Follow Week 52 
Schedule of 
Procedures at ET; 
Patient strongly 
encouraged to visit 
clinic for 
post-treatment 
assessments 
TREATMENT PERIOD 
 
Weeks 1 to 52 
 
Once Weekly 300 mg SC injection of 
volanesorsen.  Routine safety assessments.  
PK and PD/efficacy assessments at 
specified time points 
POST-TREATMENT EVALUATION 
PERIOD 
 
Weeks 53 to 65 
 
2 clinic visits for safety, efficacy, PK and 
PD assessments 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ADA 
anti-drug antibody 
AE 
adverse Event 
ALP 
alkaline Phosphatase 
ALT 
alanine Aminotransferase 
ANA 
antinuclear Antibody 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
apoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
DNA 
deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HAPI 
Heritability and Phenotype Intervention 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein-Cholesterol 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IDL 
Intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IM 
immunogenicity 
Index Study 
ISIS 304801-CS6 


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INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web-Response System 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein-Cholesterol 
LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
NOAEL 
No-Observed-Adverse-Effect Level 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
OLE 
Open Label Extension 
OTC 
over the counter 
PFS 
prefilled syringe 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
Tmax 
time to maximal concentration 
TG 
triglycerides 
Treatment emergent 
occurring after first dose of study drug 
TRL 
Triglyceride-Rich Lipoproteins 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very-Low-Density Lipoprotein-Cholesterol 
VLDL-TG 
Lipoprotein-Triglyceride 
WMA 
World Medical Association 
 
 
 


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1. 
OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of extended dosing with 
volanesorsen in patients with familial chylomicronemia syndrome. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia, and risk or history of pancreatitis.  It is a rare 
autosomal recessive disease that can be diagnosed either in childhood or adulthood. 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Patients with FCS often present in 
infancy or childhood with frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia 
retinalis and hepatosplenomegaly, and plasma from patients appears lactescent, interfering with 
determination of other laboratory parameters (Tremblay et al. 2011). 
Patients with fasting triglyceride levels > 10 mmol/l probably have a component of 
chylomicronemia.  Clinical diagnosis would include evidence of clinical features of 
chylomicronemia syndrome and secondary causes such as uncontrolled type 1 or type 2 diabetes 
mellitus (T2DM), hypothyroidism, poor diet, alcohol use, nephrotic syndrome or use of 
associated medications should be ruled out.  The diagnosis of FCS may be made more 
specifically by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) 
enzyme activity in post heparin plasma (Brunzell 1999-2011). 
Patients with FCS carry a heavy burden of medical complications, the most serious, as described 
above, being an extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent 
episodes of acute pancreatitis, these patients may also develop chronic pancreatitis and signs of 
exocrine or endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  
While the pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, one hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed 
to pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides (TG) in chylomicrons along the luminal surface of capillaries, mainly in heart, 
skeletal muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL 
is regulated by a number of key genes, and loss-of-function mutations in one of these genes, or 
the LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function 
mutations, null mutations, and nonsense mutations in the LPL gene, other genes currently 
identified in FCS patients, and known to directly influence LPL activity include: 
apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V 


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(APOA5) an enhancer of LPL activity (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a 
transmembrane protein involved in LPL maturation (Doolittle et al. 2009); 
glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma triglyceride levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Ooi et al. 2008; Figure 1).  ApoC-III is a major 
regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of triglyceride-rich lipoproteins (TRLs) and a potent 
inhibitor of LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic 
lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very-low-density lipoprotein (VLDL) to intermediate density lipoprotein 
(IDL) and to LDL (Mendivil et al. 2010), as well as in the remodeling of HDL  
(Brown et al. 2010).  In addition, increased apoC-III content adversely affects apoE-mediated 
hepatic uptake of TG-rich remnants (Mann et al. 1997).  Thus, elevated plasma apoC-III levels 
are associated with impaired hydrolysis and retarded clearance of TG-rich particles, resulting in 
the accumulation of lipoprotein-triglyceride (VLDL-TG) and chylomicrons in plasma and the 
development of hypertriglyceridemia (Ito et al. 1990). 
 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 


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Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive phenotypic associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  In 
contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma TG, 
apoC-III polymorphisms associated with higher plasma TG have also been recently described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
plasma TG from the circulation.  Taken together, the available data strongly support the 
development of a therapy that reduces plasma apoC-III levels in order to reduce the very high 
circulating triglyceride and chylomicron levels that are accompanied by increasing risk for acute 
pancreatitis. 
Given the profound reductions in TGs observed with volanesorsen treatment in FCS patients 
who have no detectable LPL activity (See Section 2.3.4), and the mechanistic data available to 
date on apoC-III function, potential mechanisms that explain how apoC-III inhibition results in 
triglyceride reduction in FCS patients include:  (1) enhancing the very small residual amounts of 
LPL activity that these patients may have, below the limit of detection of the assay in many cases 
(2) potentially enhanced activity of other lipases also involved in the metabolism and breakdown 
of TGs, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and 
(3) apoC-III interaction with Apolipoprotein E (apoE), an important factor in liver reuptake of 
lipid particles by blocking apoE-mediated uptake of lipid particles in the liver  
(Breyer et al. 1999), and therefore, reducing apoC-III might enhance apoE-mediated uptake of 
lipid particles.  Volanesorsen-mediated reduction of apoC-III could be contributing to one or all 
of these mechanisms resulting in the observed potent and sustained reductions in TG. 
Through a novel apoC-III lowering mechanism of action, volanesorsen may provide the potential 
to manage triglyceride levels in FCS patients. 
2.3 
Volanesorsen 
2.3.1 
Mechanism of Action 
Volanesorsen is a second-generation antisense oligonucleotide (ASO) drug targeted to human 
apoC-III.  It is complementary to a region within the 3ʹ untranslated region of the apoC-III 
messenger ribonucleic acid (mRNA) and binds to the mRNA by Watson and Crick base pairing.  


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The hybridization (binding) of volanesorsen to the cognate mRNA, results in the RNase 
H1-mediated degradation of the apoC-III mRNA, thus preventing production of the apoC-III 
protein.  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, volanesorsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of volanesorsen 
(Figure 2) is complementary to a 20-nucleotide stretch within the 3ʹ untranslated region of the 
apoC-III mRNA transcript at base position 489-508.  Structurally, the oligonucleotide has 
3 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are 
composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified ribonucleotides.  These MOE-modified 
nucleotides confer (1) increased affinity to the target mRNA (Altmann et al. 1996;  
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and volanesorsen 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity.  
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalysis of RNA hybridized to 2ʹ-MOE-modified nucleotides  
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2ʹ-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2ʹ-MOE chemistry 
are preserved while also retaining RNase H1 recognition. 
 
 
Figure 2 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of volanesorsen is shown 
2ʹ-MOE 
2′-Deoxy 
2′-MOE 
(RNase H 
Sensitive)
A  G  C T T
C  T T G T C C A G C 
T T T A T
Phosphorothioate
Backbone 


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2.3.3 
Preclinical Experience 
Inhibition of apoC-III using volanesorsen has been shown to potently reduce hepatic apoC-III 
mRNA as well as plasma apoC-III protein and TG in a dose- and time-dependent fashion in 
several species, including human apoC-III transgenic mice, and other rodent and monkey 
models.  Treatment with volanesorsen also resulted in reduced VLDL and chylomicron TG and 
reduced postprandial TG in hypertriglyceridemic monkeys (Graham et al. 2013). 
The pharmacokinetics (PK) and toxicity of volanesorsen have been assessed in mice, rats, and 
cynomolgus monkeys.  General toxicity studies with volanesorsen for up to 39 weeks of 
treatment followed by up to a 20-week recovery period are complete.  The preclinical toxicology 
program for volanesorsen consists of single dose safety pharmacology studies in the monkey 
(cardiovascular) and mouse (neurobehavioral and pulmonary assessment studies), in vitro and 
in vivo genetic toxicity assessment, repeat dose fertility and/or developmental reproductive 
toxicology studies in the mouse and rabbit and evaluation in the in vitro human  
Ether-á-go-go-related gene (hERG) assay. 
Volanesorsen treatment-related findings in mice and monkeys were generally consistent with 
those expected for the 2′-MOE-class of ASOs.  Treatment-related findings included effects 
consistent with drug accumulation in tissues in rodents and monkeys, species-dependent 
proinflammatory response in rodents and monkeys and complement activation and reductions in 
platelet counts in the monkey.  In the mouse and monkey general toxicity studies, reduction of 
hepatic apoC-III mRNA (> 75%) was not associated with any findings that could be considered 
related to the pharmacologic inhibition of apoC-III for up to 39 weeks of treatment. 
The long-term, chronic toxicology studies in rodents with volanesorsen produced a significant 
proinflammatory response that led to subsequent effects on the heart at high doses.  The rodent 
species are most sensitive to the proinflammatory effects of antisense molecules.  Importantly, 
these effects on the heart were not observed in the monkey chronic toxicity studies even at the 
highest doses tested where drug exposure was higher than that in rodents. 
Because these changes were not observed in monkeys, the findings in the heart are considered to 
be rodent-specific and not relevant to humans.  Nevertheless, such effects will be monitored by 
measurement of echocardiograms that will be included in this clinical study. 
Volanesorsen caused no untoward effects in safety pharmacology studies (in vitro and in vivo) 
and was non-genotoxic (in vitro and in vivo).  Volanesorsen had no effects on fertility or 
embryo/fetal development in the mouse or rabbit reproductive toxicity studies.  In these studies, 
volanesorsen was detected in placental tissue but not in fetal tissue indicating that little, if any, 
drug was able to cross the placenta to reach the fetus.  Reduction of apoC-III mRNA (64% in 
males and 47% in females) also did not affect fertility or cause untoward effects on embryo/fetal 
development in mice. 
Detailed information concerning the preclinical studies conducted with volanesorsen can be 
found in the volanesorsen Investigator’s Brochure. 


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2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with volanesorsen can be found 
in the volanesorsen Investigator’s Brochure.  A summary is included below. 
Volanesorsen has been evaluated in one Phase 1 study and two Phase 2 studies, all double 
blinded and placebo controlled.  The total exposures comprise 99 patients and healthy volunteers 
administered volanesorsen from 50 to 400 mg subcutaneously up to 3 months (compared to 
37 administered placebo). 
All clinical trials of volanesorsen have shown large and clinically meaningful reductions in 
fasting plasma apoC-III and TG (~80% and 70%, respectively, mean reduction from baseline 
with 300 mg dose) with a very high degree of consistency of response between the different 
patient groups.  This includes healthy volunteers, patients with moderate to severe 
hypertriglyceridemia not on background TG-lowering therapy, patients with moderate to severe 
hypertriglyceridemia on a background stable fibrate therapy (Gaudet et al. 2015), patients with 
FCS, and patients with T2DM. 
In a Phase 2 study, three patients with FCS were treated with 300 mg/wk volanesorsen in an 
open label fashion.  These patients had a mean baseline fasting TG level of 1,844 mg/dL and all 
three patients achieved TG levels below or close to 500 mg/dL during the dosing period out to 
Day 92 (Figure 3).  Two (2) of the FCS patients had an absolute reduction in fasting TG in 
excess of 1,500 mg/dL (Gaudet et al. 2014). 
 
Figure 3 
Fasting Triglycerides in Patients with FCS Treated with Volanesorsen 


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In clinical studies conducted to date volanesorsen has been well tolerated and has shown a 
favorable safety profile.  There has been no clinical or laboratory evidence of drug-drug 
interactions. 
To date, there have been no volanesorsen associated laboratory abnormalities suggestive of an 
effect on the renal (serum creatinine, proteinuria) or hepatic systems (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], bilirubin) despite many patients in the Phase 2 clinical 
trials receiving concomitant medications that are known to be associated with elevations in 
hepatic enzymes, such as fibrates and statins.  In Phase 2 studies, there was a mild decrease of 
platelet count associated with volanesorsen administration that recovered in the post-treatment 
period and was not associated with platelet-related adverse events (AEs). 
The most frequently observed AEs with volanesorsen were local reactions at the injection site.  
Local cutaneous reactions at the injection site defined as those events presenting as either pain, 
tenderness, erythema, pruritus or swelling occurring on the day of injection and persisting for at 
least 2 days were infrequent (~15% of injections), were almost always mild, resolved 
spontaneously, were non-progressive, and were not associated with systemic sequelae. 
2.4 
Rationale for Dose and Schedule of Administration 
The dose and schedule selected for this study is 300 mg per week for 52 weeks.  The dose of 
300 mg per week is supported by both the cumulative nonclinical data available to date and the 
Phase 2 clinical data.  In nonclinical studies, volanesorsen treatment-related effects in rodents 
and monkeys were consistent with drug accumulation in tissues and also include species-specific 
proinflammatory responses.  In the monkey, the No-Observed-Adverse-Effect Level (NOAEL) 
was defined by the cumulative clinical pathology results and histopathology data which provide 
an adequate clinical margin.  No nonclinical findings were considered to be related to the 
pharmacologic inhibition of apoC-III. 
The safety data to date suggest that volanesorsen has been well tolerated at dose levels up to 
300 mg in patients with high triglycerides (including type 2 diabetes patients and administration 
in combination with fibrates and statins) with the most common AEs being local to the injection 
site and predominantly mild.  A pooled analysis of safety for the Phase 2 studies did not 
demonstrate any clear difference in safety or tolerability between the different doses tested 
(100 mg, 200 mg, and 300 mg per week for 13 weeks). 
Analysis of the cohorts in which volanesorsen was studied at different doses demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic (PD) effect on the target, 
apoC-III, with a clear difference in the TG-lowering effect between the different doses in the 
100 mg to 300 mg dose range as compared to placebo. 
In addition to the nonclinical and clinical experience of volanesorsen, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified ASOs that have been safely administered intravenously and subcutaneously in 
multiple clinical studies at doses up to 1000 mg and for treatment durations that exceed 
24 months (Santos et al. 2015). 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label extension to the Phase 3 study of volanesorsen in patients with FCS 
(ISIS 304801-CS6).  Up to approximately 50 patients will receive 300 mg once weekly 
volanesorsen for 52 weeks. 
Following the Week 52 visit, patients enter a 13-week post-treatment evaluation period. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Up to approximately 50 patients will be dosed. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of the following periods: 
• A qualification period of up to 2 weeks (unless approved by the Sponsor)  
• A 52-week treatment period during which volanesorsen will be administered as a once 
weekly SC injection 
• A 13-week post-treatment evaluation period 
Please refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Qualification 
A period of up to 2 weeks is given to complete qualification assessments outlined in the 
Schedule of Procedures (Appendix A). 
3.4.2 
Treatment 
The treatment period is 52 weeks.  Eligible patients will report to the Study Center for 
assessments at specified intervals throughout the 52-week treatment period as detailed in the 
Schedule or Procedures (Appendix A).  During the treatment period, volanesorsen is 
administered by SC injection once weekly. 
3.4.3 
Post-Treatment 
The post-treatment evaluation period is 13 weeks and consists of two Study Center visits on 
Weeks 58 and 65. 
3.5 
End of Study 
The end of study is last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will review (as needed) safety, tolerability and 
efficacy data collected on volanesorsen during this study.  Based on its ongoing assessment of 


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the safety and tolerability of volanesorsen, the DSMB will provide recommendations to the 
Sponsor for modifying, stopping or continuing the study as planned.  Details on the safety 
assessments, frequency of review and meeting schedules are outlined in the DSMB Charter 
and/or the statistical analysis plan (SAP). 
4. 
PATIENT ENROLLMENT 
4.1 
Qualification  
Before patients may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other patient information. 
Final assessments from the index study may be used for qualification as long as they were 
conducted within 4 weeks of the qualification period.  Patients or their legally acceptable 
representatives must sign the consent form before any study-specific procedures or evaluations 
related to this open label study are performed.  During the qualification period, the eligibility of 
the patient to continue in the extension study will be determined.  A period of up to 2 weeks after 
completion of the index study (unless approved by the Sponsor) is given to complete 
qualification.  Qualified patients will retain the unique patient identification number that was 
assigned to them during the index study.  The patient identification number will be used to 
identify the patient throughout the extension trial and must be used on all study documentation 
related to that patient.  The patient identification number must remain constant throughout the 
extension trial. 
4.2 
Enrollment 
Patients will be enrolled after all qualification assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No patient 
may begin treatment prior to enrollment. 
Eligible patients will be enrolled using an Interactive Voice/Web-Response System (IXRS). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 2 weeks of Study Day 1, or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must give written informed consent to participate in the study (signed and dated) and any 
authorizations required by law 
2. Age ≥ 18 years at time of informed consent 
3. Satisfactory completion of ISIS 304801-CS6 (index study) with an acceptable safety 
profile, per Sponsor and Investigator judgment 
4. Able and willing to participate in a 65-week study 
 


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5. Satisfy one of the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal 
(defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory 
involved), abstinent, or if engaged in sexual relations of child-bearing potential, 
patient is using an acceptable contraceptive method (refer to Section 6.3.1) from time 
of signing the informed consent form until 13 weeks after the last dose of Study Drug 
administration. 
b. Males:  Surgically sterile, abstinent or if engaged in sexual relations with a female of 
child-bearing potential, patient is utilizing an acceptable contraceptive method (refer 
to Section 6.3.1) from the time of signing the informed consent form until 13 weeks 
after the last dose of Study Drug administration. 
5.2 
Exclusion Criteria 
1. Have any new condition or worsening of existing condition which in the opinion of the 
Investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
2. Unwilling to comply with lifestyle requirements for the duration of the study 
(Section 6.3). 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, C, and D. 
6.1.1 
Qualification 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  A 2-week period is given after the index study to complete the 
qualification assessments.  The qualification assessments will be performed at Week -2 to -1, 
ideally after patient eligibility has been determined, and on Study Day 1.  Abnormal results may 
be retested for review by the Study Medical Monitor for eligibility purposes.  Final assessments 
from the index study may be used for qualification as long as they were conducted within 
4 weeks of the qualification period. 
6.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through 
the last patient’s Week 13 visit of the index study or until results from database lock for the 
index study becomes available, whichever comes first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 
10 times during Weeks 1-52 (see Schedule of Procedures in Appendix A).  Study Drug will be 
administered once weekly (Section 8.1).  Collection and measurement of vital signs, clinical 
laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, 


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concomitant medication/procedure information, lipid panel, volanesorsen plasma concentrations, 
immunogenicity (IM) testing, liver/spleen MRI, ECGs, echocardiograms and quality of life 
assessments will be performed according to the schedule of procedures in Appendix A.  Adverse 
events at the injection site should be collected as adverse events.  Dietary counseling will be 
reinforced at intervals throughout the treatment and follow-up period and all patients will 
complete a daily food diary for one week prior to their quarterly visit.  All blood and urine 
samples should be collected prior to volanesorsen administration.  Blood sampling for lipid 
panels at Weeks 12, 25 and 51 may be conducted by a home healthcare nurse if more convenient 
for the patient.  Patients must be fasted prior to drawing all blood samples and samples drawn 
locally must be sent to the central laboratory for analysis.  Every effort should be made to ensure 
the previous week’s dose is given 7 days prior to a scheduled clinic visit.  Dosing instructions 
and training will be provided to the patient where applicable. 
All visits have a visit window of at least ± 2 days.  All reasonable attempts should be made to 
ensure compliance with the visit schedule as outlined in Appendix A.  However, in the event that 
a visit does not occur or is delayed, all subsequent visits should be calculated based on the time 
elapsed since Day 1 rather than from the date of the previous visit. 
6.1.3 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup 
will have more frequent PK sampling over a 24-hour period following the first dose on 
Study Day 1 in order to evaluate the plasma PK parameters of volanesorsen.  Patients in this 
subgroup will have an additional visit to the clinic on Day 2 to collect a 24-hour post-dose blood 
draw after dosing on Day 1.  The detailed PK sampling schedules are outlined in Appendix C. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being 
withdrawn from the study.  If a patient withdraws consent from the subgroup procedures, he/she 
should remain on study and continue to follow all the non-subgroup assessments and procedures 
as outlined in Appendix A. 
6.1.4 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will enter the 13-week 
post-treatment evaluation period.  This period consists of two Study Center visits on Weeks 58 
and 65 as outlined in the Schedule of Procedures in Appendix A. 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study. 
A list of these analytes is contained in Appendix B. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a 


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sitting position for at least 5 minutes.  Semi-supine systolic and diastolic blood pressure should 
always be measured on the same arm (preferentially on the left arm).  Height will be measured at 
the Day 1 visit. 
6.2.3 
Echocardiography 
Echocardiography for assessment of left and right ventricular function and mitral and aortic 
valve function will be conducted at Week 26 and Week 52 in all patients.  For the purpose of 
assessment of treatment emergent changes, all echocardiograms will be evaluated on an ongoing 
basis by an independent central reader.  Results will be provided to the DSMB for their review. 
6.2.4 
ECG 
The ECG will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate at Week 13, Week 26, Week 38, Week 52, and 
Week 65. 
6.2.5 
MRI 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. 
MRIs will be conducted using standardized procedures and settings.  MRIs will be read by an 
independent central reader to assess liver fat and liver and spleen size. 
6.2.6 
Quality of Life Assessments 
All patients will complete Quality of Life Questionnaires (EQ-5D and SF-36) at Week 13, 
Week 26 and Week 52. 
6.2.7 
Disease Symptom Diary  
All patients will complete a symptom questionnaire once a week starting at the beginning of the 
qualification period and continuing to the end of the post-treatment follow-up period. 
6.2.8 
Diet Monitoring 
All patients will be required to maintain a 7-day food diary at Week 1, Week 13, Week 26, and 
Week 52.  Inquiries from a dietitian as to how each patient is maintaining their diet will be 
conducted randomly during the treatment and post treatment follow-up periods.  Counseling will 
also be provided at home visits. 
 6.2.9 
Family History 
Family history of hypertriglyceridemia and pancreatitis will be collected for each patient. 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
practice effective contraception from the time of signing the informed consent form until at least 
13 weeks after their last dose of study treatment. 


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Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent until 13 weeks after the subject’s last dose of study 
treatment. 
For the purposes of this Study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet one of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male patients: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository.  Male patients must also encourage their female partner to use 
effective contraception from the time of signing the informed consent until 3 months after 
the patient’s last dose of study treatment.  Effective contraceptive for the female partner 
includes: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception, 
intrauterine contraception/device, or barrier methods (female condom*, diaphragm, 
sponge, cervical cap) together with spermicidal foam/gel/film/cream/suppository.  Male 
patients with partners that are pregnant must use condoms to ensure that the fetus is not 
exposed to the study drug. 
For female patients: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. 
*Note: A female condom and a male condom should not be used together as friction between 
the two can result in either product failing. 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours before visits requiring fasted blood 
sampling. 
All patients will be encouraged to follow a diet comprising ≤ 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 


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All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event, 
based on Atlanta Classification (Banks et al. 2013).  If serum or amylase activity is less than 
3 x upper limit of normal (ULN), imaging, preferably contrast-enhanced computed tomography, 
should be considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1 
Volanesorsen Description 
Volanesorsen drug product (ISIS 304801) characteristics are listed in Table 1. 
Volanesorsen (ISIS 304801) is contained in glass prefilled syringes (PFS).  Volanesorsen and its 
storage and preparation instructions will be provided by the Sponsor or designee.  Volanesorsen 
must be stored securely at 2° to 8° C and be protected from light. 
Table 1 
Volanesorsen (ISIS 304801) Characteristics 
Strength 
200 mg/mL  
Volume/Formulation 
1.5 mL solution per PFS  
Dose 
300 mg once weekly 
Route of Administration 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged volanesorsen labeled (ISIS 304801) in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen provided by the Sponsor.  The Study Center must return all unused volanesorsen to 
the Sponsor or designee.  All used syringes must be disposed of as per the site’s hazardous waste 
destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Volanesorsen Administration 
For each individual patient, volanesorsen will be administered subcutaneously as a single 1.5 mL 
injection once weekly for Weeks 1-52. 
Patients should receive 1 dose per week, with weeks always defined relative to Study Day 1.  For 
example if a patient receives the first dose on a Monday, subsequent doses should be given on 
Mondays, if possible.  If a patient misses an injection, or if dosing on the usual day is not 


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possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous week’s dose is given 7 days prior to a 
scheduled clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
volanesorsen preparation and administration. 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs (Section 6.2.5). 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol required treatment procedures for this study. 
8.4 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from final visit of the index study if used for qualification). 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring or stopping criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens.  All new specimen collections should 
take place as soon as possible (ideally within 3 days of the initial collection).  For stopping rules, 
if the initial laboratory result is observed during the Treatment Period, the results from the retest 
must be available prior to administering the next dose of volanesorsen. 
In addition to the safety monitoring parameters listed below, the Sponsor may request 
confirmation of additional lab values. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
below (refer to Sections 8.6.1 to 8.6.3) are met, the patient will be permanently discontinued 
from further treatment with volanesorsen, evaluated fully as outlined below and in consultation 
with the Sponsor Medical Monitor or appropriately qualified designee, and will be followed up 
in accordance with Section 8.8 of the protocol. 


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8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 x ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN (or 
the greater of 2 x baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 x ULN or 1.2 x baseline value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 x ULN. 
8.5.2 
Safety Monitoring Rules for Platelet Count Results 
If a patient’s platelet count falls by 30% or greater from baseline and the absolute platelet count 
is 75,000/mm3 or less, then the patient’s platelet counts should be monitored more frequently.  
The frequency of monitoring and additional lab tests will be determined by the Investigator in 
consultation with the Sponsor Medical Monitor or designee. 
8.5.3 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically 
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 


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bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR and 
platelet count should be performed. 
8.5.4 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs of symptoms of fever or constitutional 
symptoms that may arise during the study and the Investigator should closely evaluate all 
potential causes, including concomitant illness.  Patients that experience persistent constitutional 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine 
whether additional monitoring or laboratory tests are required. 
8.5.5 
Safety Monitoring for LDL-C Elevations 
Beginning at Week 13, laboratory alerts will be in place to notify the Investigator if a patient has 
a low-density lipoprotein-cholesterol (LDL-C) > 160 mg/dL (> 130 mg/dL for patients with 
T2DM) on two consecutive visits.  If this occurs, LDL-C values for this patient will be unblinded 
for the remainder of the study and the Investigator will be encouraged to initiate/adjust treatment 
to lower LDL-C according to country-specific guidelines (e.g., initiate statin therapy or increase 
the statin dose for patients who are already on treatment). 
8.5.6 
Acute Pancreatitis 
If a patient has an episode of acute pancreatitis, dosing with study drug should be suspended 
temporarily until the patient is clinically stable.  The suitability of the patient for continued 
dosing and the need for any modification to treatment schedule (refer to Section 8.7) will be 
determined by the Investigator in consultation with the Study Medical Monitor. 
8.6 
Stopping Rules 
For the purposes of stopping rules baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with volanesorsen will be stopped permanently; values that are not confirmed due to failure to 
retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks   
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
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8.6.2 
Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for any of the 
three criteria below, dosing of a patient with volanesorsen may be stopped temporarily: 
1. Serum creatinine increase that fulfill all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
3. Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault ≤ 40 mL/min that is confirmed by a 24 hour urine collection 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
8.6.3 
Stopping Rule for Platelet Count Results 
In the event of a platelet count less than 50,000/mm3that is associated with major bleeding or 
clinically relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen will be stopped permanently.  The follow-up schedule for any events meeting 
this stopping criterion will be determined by the Investigator in consultation with the Sponsor 
Medical Monitor. 
In the event of a platelet count less than 50,000/mm3, and in the absence of major bleeding or 
clinically relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient 
with volanesorsen should be suspended temporarily until the platelet count has recovered to 
≥ 100,000/mm3.  The suitability of the patient for continued dosing and the need for any 
modification to treatment schedule (refer to Section 8.7) will be determined by the Investigator 
in consultation with the Study Medical Monitor and will be based on factors such as the original 
rate of decline in the patient’s platelet count, whether any bleeding events were experienced by 
the patient, and the speed of recovery of platelet count upon holding of dosing. 
If after the first dosing re-challenge the platelet count again falls below 50,000/mm3, then dosing 
of the patient must be held until the platelet count again returns to at least 100,000/mm3.  The 
suitability of the patient for continued dosing and the need for any further modification to 
treatment schedule or dose (refer to Section 8.7) will be re-examined by the Investigator in 
consultation with the Study Medical Monitor based on (at least) the factors mentioned above. 
If after the second re-challenge the platelet count falls below 50,000/mm3 and is subsequently 
confirmed (see Section 8.5), dosing with volanesorsen will be stopped permanently.  The 
follow-up schedule for any events meeting this stopping criterion will be determined by the 
Investigator in consultation with the Study Medical Monitor. 


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Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of two or more units of whole or red cells 
Definition of Clinically Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
8.7 
Adjustment of Dose Frequency 
Dose adjustments, including dose interruptions, and/or decreasing the dose frequency will be 
allowed for safety and tolerability.  Any proposed adjustment to treatment schedule must be 
discussed with, and approved by, the Study Medical Monitor prior to initiation.  Up to two 
adjustments in the treatment schedule may be allowed for patients that are unable to tolerate the 
once weekly dose (for example if platelet counts fall below 50,000/mm3 as described in 
Section 8.6.3).  If the patient remains stable after adjustment, they may be cautiously returned to 
the original once weekly regimen after consultation with the Study Medical Monitor. 
Patients may be dose paused in response to AEs after consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of study 
treatment 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 


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8.8.1 
Follow-up Visits for Early Termination from Treatment Period 
Any patient who discontinues early from the Treatment Period should be strongly encouraged to 
attend applicable landmark visits at Weeks 12, 13, 25, 26, and 51, 52 (calculated based on the 
time elapsed since Day 1) to collect fasting lipid panels and conduct safety assessments in 
accordance with the schedule of procedures in Appendix A.  Any patient who discontinues 
treatment after Week 44 should also be strongly encouraged to attend a final follow-up visit 
(Week 65 visit assessments) approximately 13 weeks after their last dose of Study Drug, in 
addition to the applicable landmark visits. 
If the patient declines or is unable to participate in the above, an early termination (ET) visit 
(Week 52 visit assessments) should be performed at the time of withdrawal, at a minimum, and 
ideally within 2 weeks from the last dose of Study Drug. 
8.8.2 
Follow-up Visits for Early Termination from Post-Treatment Follow-up Period 
The patient who requests to withdraw from the study during the Post-Treatment Follow-up 
Period should be encouraged to undergo a final follow-up visit (Week 65, see Appendix A) prior 
to leaving the study. 
If a patient withdraws due to an AE at any time during the study, the Investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from Study, must 
be recorded in the CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the ET study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Section 8.8 and Appendix A). 


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8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
informed consent and completion of the post-treatment follow-up period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a patient, including changes in the patient’s current medications, must be 
recorded in the patient’s source documents and CRF.  Patients taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), glucacon-like peptide-1 (GLP-1) agonists, Glybera, or 
systemic corticosteroids may be started or adjusted after baseline qualification.  Doses of existing 
oral anti-diabetic medication, oral contraceptives, hormone replacement therapy, anticoagulants, 
or drugs or dietary supplements with potential lipid-altering effects should not be adjusted.  
Study patients are prohibited from receiving other experimental agents during the study.  This 
includes marketed agents at experimental dosages that are being tested for the treatment of 
hypertriglyceridemia. 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and Week 65 visit. 
Disallowed Concomitant Procedure 
Plasma apheresis is not allowed during the study. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
volanesorsen.  Patients that are self-administering volanesorsen at home must record treatment in 
a dosing diary that will be reviewed periodically by Study Center staff and the Clinical Monitor. 


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9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions 
(SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and ICH 
E6.  Country-specific regulatory requirements will be followed in accordance with local country 
regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The Data and Safety Monitoring Board (DSMB) will 
be notified of any SAE as specified in the DSMB charter. 
The Sponsor or designee will evaluate the available information and decide if there is a 
reasonable possibility that volanesorsen caused the AE and, therefore, meets the definition of a 
SUSAR. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of volanesorsen exposure.  The Investigator still has the responsibility to 
report all SAEs to the Sponsor as described in Sections 9.4.1 to 9.4.3.5. 
Table 2 
Expected Event for the Protocol Defined Population by Preferred Term and 
the Expected Incidence 
Preferred Term 
Expected Incidence in the Protocol Defined 
Population (Gaudet et al. 2010 and 2013) 
Pancreatitis associated events including the PTs of 
hereditary pancreatitis, pancreatitis, pancreatitis 
acute, pancreatitis chronic, pancreatitis necrotizing, 
pancreatitis relapsing 
0.2-0.35 events per patient-year  
 
Fatal pancreatitis associated events will be considered as unexpected and are reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-volanesorsen exposed population.  If the 
aggregate analysis indicates that an event is occurring significantly more frequently or at a 
greater severity than expected, then the event will be reported. 
SAEs not specified in the table will be evaluated on case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR the event will be reported. 


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9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by volanesorsen. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
volanesorsen drug caused the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening: that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 


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9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to volanesorsen) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s 
follow-up period which is defined as the Week 65 visit.  When the Investigator is reporting by 
telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or 
designee. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as the Week 65 visit.  
The Investigator will monitor each patient closely and record all observed or volunteered AEs on 
the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to volanesorsen is characterized by one of the following: 
• Related:  There is clear evidence that the event is related to the use of volanesorsen e.g., 
confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and volanesorsen administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
volanesorsen administration and/or exposure suggests that a causal relationship is 
unlikely (For reporting purposes, Unlikely/Remote will be grouped together with Not 
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• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and volanesorsen 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Volanesorsen 
Action taken with volanesorsen due to the event is characterized by one of the following: 
• None:  No changes were made to volanesorsen administration and dose 
• Permanently Discontinued:  Volanesorsen was discontinued and not restarted 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted 
or delayed due to the AE and restarted at the same dose 
• Reduced schedule:  Dosing frequency was reduced 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures CRF as appropriate). 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by one of the 
following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 


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If the event is a SAE then the event’s outcome is characterized by one of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.4.4 
Adjudication Committees 
All SAEs that occur during the study that are consistent with a major acute cardiovascular event 
(MACE) will be adjudicated by a blinded, independent committee as outlined in the MACE 
Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for prior episodes of acute pancreatitis or suspected 
pancreatitis will be collected by review of each patient’s medical chart and these events will also 
be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 


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• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Volanesorsen dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of volanesorsen that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with volanesorsen.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known  (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 


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Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
For fasting lipid measurements, the values at Month 3 analysis time point are defined as the 
average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments, the values of Month 6 
analysis time point is at the end of Month 6 are defined as the average of Week 25 (Day 169) and 
Week 26 (Day 176) fasting assessments, and the values at the Month 12 analysis time point are  
defined as the average of Week 51 (Day 351) and Week 52 (Day 358) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Frequency and severity of patient reported abdominal pain during the treatment period 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 [apoA-1], VLDL-C, 
and LDL-C 
• Percent change from baseline in fasting total apolipoprotein C-III  
• Quality of Life questionnaires (EQ-5D, SF-36) 
• Adjudicated acute pancreatitis event rate 
10.1.2 
Safety Endpoints  
• Adverse events including adjudicated events of pancreatitis and MACE 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiography 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
• MRIs 


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10.2 
Sample Size 
No sample size calculations were performed as this is an extension study to the double-blind, 
placebo-controlled ISIS 304801-CS6 study.  Approximately 50 patients may be eligible to enroll 
into this study. 
10.3 
Populations 
Full Analysis Set (FAS):  All patients who are enrolled and have a baseline TG assessment.  The 
FAS represents the practically-feasible intent-to-treat (ITT) population as delineated in ICH 
Guideline E9. 
Per Protocol Set (PPS):  Subset of the FAS who received 9 of first 13 scheduled doses of 
volanesorsen and with no significant protocol deviations that would be expected to affect 
efficacy and PD assessments.  The detailed criteria will be specified and finalized prior to the 
final database lock. 
Safety Set:  All patients who are enrolled and receive at least one dose of volanesorsen. 
PK Population:  All patients who are enrolled, receive at least one dose of volanesorsen, and 
have at least one evaluable PK sample collected, analyzed, and reported. 
10.3 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, two baselines are defined for each patient: index study baseline 
and the baseline in this open label study, which is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1 (e.g., qualification assessments or 
assessments from final visit of the index study if used for qualification). 
For other measurements, baseline for patients on active treatment in the index study will be the 
index study baseline.  For patients on placebo in the index study, baseline for safety will be the 
last non-missing assessment prior to the first dose of Study Drug. 
10.4 
Interim Analysis  
An interim analysis may be conducted after the database of index study is locked and unblinded.  
Both safety and efficacy information from this study may be summarized during this interim 
analysis.  Efficacy analyses will be detailed in the SAP. 
10.5 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data by treatment group.  Where appropriate, p-values 
will be reported.  All statistical tests will be conducted using 2-sided tests with 5% Type I error 
rates unless otherwise stated. 


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All efficacy endpoints will be assessed in the FAS and PPS.  All safety assessments will be 
performed on the Safety Set.  PK endpoints will be assessed in the PK Set as applicable. 
10.5.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group of the index 
study.  All patients enrolled will be included in a summary of patient disposition. 
10.5.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
of the index study. 
Patient incidence rates of AEs will be tabulated by MedDRA system organ class, MedDRA 
preferred term, and treatment group of the index study.  Narratives of treatment emergent deaths, 
serious and significant AEs, including early withdrawals due to AEs, will also be provided. 
All treatment emergent AEs, all treatment emergent AEs potentially related to Study Drug, all 
treatment emergent serious AEs, and all treatment emergent serious AEs potentially related to 
Study Drug will be summarized. 
Injection Site Reactions (ISRs) will be summarized by treatment group of the index study, 
MedDRA preferred term and severity. 
Independently adjudicated events of MACE and pancreatitis will be summarized by treatment 
group of the index study. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, IM, complement etc., will be summarized by study visits by 
treatment group of the index study.  These safety variables will also be presented as change and 
percent change from baseline over time after study drug administration, as appropriate. 
Vital signs, weight, ECG measures, echocardiography assessments, and MRI assessments will be 
tabulated by treatment group of the index study. 
10.5.3 
Efficacy Analysis 
Percent change and change from baseline to Month 3, Month 6, and Month 12 in fasting TG will 
be summarized by treatment group of the index study.  Response rate of patients with fasting 
plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at Month 3, 
Month 6, and Month 12 will be summarized.  Response analysis will also be conducted using a 
range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3, Month 6, and Month 12 will also be 
summarized by treatment group of the index study for other fasting lipid measures including 
non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and LDL-C, total cholesterol, and fasting total 
apoC-III. 


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The incremental effects of volanesorsen on lipid measures will be explored and the association 
between changes in lipid parameters and total amount of drug received will be examined, as 
appropriate. 
Frequency and severity of patient reported abdominal pain, adjudicated acute pancreatitis event 
rate, and quality of life assessments will be summarized by treatment group of the index study. 
Additional details of the analyses to be conducted will be provided in the SAP. 
10.5.4 
Pharmacokinetic and Immunogenicity Analysis 
10.5.4.1 
Pharmacokinetic Analysis 
For all patients, pre-dose and post-treatment volanesorsen plasma concentrations will be 
summarized using descriptive statistics, with stratification by their prior treatment in Study 
ISIS 304801-CS6 and IM status. 
For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be 
carried out on each individual patient data set using data collected in the open label extension 
(OLE) study from the intensive PK subgroup, following a single dose (i.e., single-dose PK) or 
multiple doses (i.e., steady-state PK), depending on their earlier treatment in the index study.  On 
Week 1 Day 1 of the OLE study, patients who received placebo in the index study will receive 
the first treatment of volanesorsen (single-dose PK), while patients who received volanesorsen in 
the index study had been on volanesorsen treatment for twelve months, thus the PK data 
collected from these patients reflect steady-state PK.  The maximum observed drug 
concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  Area under the plasma concentration-time curve from time zero to 
24 hours (AUC0-24hr) will be calculated using the linear trapezoidal rule.  Apparent systemic 
(plasma) clearance after SC administration (CL/F0-24hr) will be calculated from CL/F0-24hr = 
Actual Dose/AUC0-24hr.  Mean residence time (MRT) from time zero to 24 hours after the SC 
administration will be calculated from the equation, MRT0-24hr = AUMC0-24hr /AUC0-24hr, where 
AUMC0-24hr is the area under the moment plasma concentration-time curve from time zero to 
24 hours after the SC administration.  Other PK parameters, as appropriate, may be determined 
or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by their prior treatment in Study ISIS 304801-CS6 and IM status.  Additional details 
regarding the PK analysis will be described in the SAP. 
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and 
results will be reported separately. 
10.5.4.2 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-volanesorsen antibodies) before, during, and after 
treatment with study drug (volanesorsen) (i.e., sample [anti-drug antibody] ADA status) will be 
listed by their prior treatment in Study ISIS 304801-CS6 and study day.  Subject ADA status 
(positive/negative or not evaluable) for all evaluable patients, along with the study day associated 


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with the first positive IM status emerged (Tfirst, i.e., onset of ADA development), the last positive 
IM status observed (Tlast), the duration of ADA response (number of days between Tfirst and Tlast) 
if appropriate, the last ADA sample collection day, and subject maximum titer if applicable, will 
be listed by their prior treatment in Study ISIS 304801-CS6 and study day.  Subjects with 
positive anti-volanesorsen antibody status may be further classified (when applicable) as being 
either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed appropriate. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by their prior treatment in Study ISIS 304801-CS6.  Furthermore, 
onset, duration, and titer of the ADA response, if applicable, will be summarized as median, 
quartiles (25% and 75%), and range. 
Additional details regarding the IM data analysis will be described in the SAP. 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy 
(e.g., % change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and PK 
(e.g., Ctrough) measures will be evaluated using graphical analysis and statistical analysis.  These 
analyses will be either conducted and included in the study report, or data pooled and analyzed 
from all available Phase II and III studies and reported separately 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific qualification 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 


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11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of volanesorsen.  A copy of 
the written approval of any other items/materials that must be approved by the Study Center or 
IEC/IRB must also be received by the Sponsor before recruitment of patients into the study and 
shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of serious adverse events 
occurring at the Study Center and other adverse event reports received from the Sponsor, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRF) or other documents submitted to the Sponsor, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor (e.g., signed informed consent forms) should be kept in strict confidence by the 
Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 


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12.2 
Study Termination 
The Sponsor reserves the right to terminate the study according to the terms of the site contract.  
The Investigator reserves the right to terminate their participation in the study, according to the 
terms of the site contract.  The Investigator/Sponsor should notify the IEC/IRB in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, CRFs 
may not be used as source documents. 
The Investigator and Study Center staffs are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor  
• If volanesorsen supplies are maintained at the Study Center, proof of receipt, 
volanesorsen Accountability Record, Return of volanesorsen for Destruction, final study 
volanesorsen reconciliation, and all volanesorsen-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 


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49 
The Sponsor monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to patient medical records and other study-related records needed to verify the entries on 
the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 


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50 
13. 
REFERENCES 
Altmann KH, Fabbrot D, Dean NM, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
humans. PLoS Biol 2006; 4: e113. 
Banks P, Bollen T, Dervenis C, et al; and Acute Pancreatitis Classification Working Group. Classification of acute 
pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62: 
102-111. 
Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding 
protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007 Apr; 5(4): 279-291. 
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine 
society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989. 
Breyer ED, Le N-A, Li X, Martinson D, Brown WV. Apolipoprotein C-III displacement of apolipoprotein E from 
VLDAL: Effect of particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
2010; 107: 357-364. 
Brunzell JD. Familial lipoprotein lipase deficiency. In Pagon RA, Adam MP, Bird TD, et al. editors. GeneReviews 
[Internet], Seattle, WA, University of Washington, Seattle; 1999-2011. 
Chan DC, Chen MM, Ooi MM, Watts GF. An ABC of apolipoprotein C-III: a clinically useful new cardiovascular 
risk factor? Int J Clin Pract 2008; 62 (5): 799-809. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev. Pharmacol Toxicol 1996; 
36: 107-129. 
Doolittle MH, Neher SB, Ben-Zeev O, et al. Lipase maturation factor 1 (LMF1): Membrane topology and 
interaction with lipase proteins in the endoplasmic reticulum. J of Biological Chemistry 2009; 1-19. 
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for 
lipoprotein lipase deficiency. Atherosclerosis Suppl 2010; 11: 55-56. 
Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene 
therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369. 
Gaudet D, Brisson, D Tremblay K, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J 
Med 371; 23 Dec, 2014; 2200-2206. 
Gaudet D, Alexander V, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia N Engl J Med 2015; 373(5): 438-447. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothiate 2′-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma 
triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013 May 24; 112(11): 1479-1490. 
Henry S, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF. Chemically modified oligonucleotides exhibit 
decreased immune stimulation in mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. Federation of European Biochemical Societies 1987; 215: 327-330. 


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51 
Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL. Hypertriglyceridemia as a result of human apo CIII gene 
expression in transgenic mice. Science 1990 Aug 17; 249: 790-793. 
Kinnunen PK and Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human 
postheparin plasma hepatic lipase. FEBS Lett 1976; 65: 354–357. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 
35: 442-448. 
Mann CJ, Troussard AA, Yen FT, et al. Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of 
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 1997; 272: 31348-31354. 
McKay RA, Miraglia LJ, Cummins LL, Owens SR, Samor H, Dean NM. Characterization of a potent and specific 
class of antisense oligonucleotide inhibitor of human protein kinase C-alpha expression. J Biol Chem 1999; 274: 
1715-1722. 
Mendivil CO, Zheng C, Furtado J, Lel J, Sacks FM. Metabolism of very-low-density lipoprotein and low-density 
lipoprotein containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol 
2010; 30: 239-245. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Ooi EMM, Barrett PHR, Chan DC, Watts GF. Apolipoprotein C-III: Understanding an emerging cardiovascular risk 
factor. Clin Sci (Lond) 2008; 114: 611-624. 
Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J 
Med 2010; 362: 1082-1089. 
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
and apparent cardioprotection. Science 2008; 322: 1702-1705. 
Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial 
hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2015 Mar; 36(9): 566-575. 
ePub 2013 Dec 23: doi: 10.1093/eurheartj/eht549. 
Schaap FG, Resen PCN, Voshol, et al. ApoAV reduces plasma triglycerides by inhibiting very low density 
lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. 
J Biol Chem 2004; 279: 27941-27947. 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Schuster KB, Wilfert W, Evans D, Thiery J, Teupser D. Identification of mutations in the lipoprotein lipase (LPL) 
and apolipoprotein C-II (APOC2) genes using denaturing high performance liquid chromatography (DHPLC). 
Clinica Chimia Acta 2011; 412: 240-244. 
Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients 
with severe hypertriglyceridaemia. J Internal Med 2012; 272: 185-196. 
Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe 
hypertriglyceridemia. J Clin Lipidol 2011; 5: 37-44. 
Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of 
isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleed risk. Blood 2010; 116: 4684-4692. 


ISIS 304801-CS7 
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52 
 
 
 
 
 
 
 
14. 
APPENDICES 
 


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53 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
 


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Appendix A Schedule of Procedures 
Study Period 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3  
Wk 
19 
Month 6 
Wk 
32 
Wk 
38 
Wk 
44 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 
50 
78 
85 127 169 176 
218 
260 
302 
351 
358 
400 
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
2 
2 
3 
3 
3 
2 
2 
7 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
X 
Xg 
X 
 
Xg 
X 
 
X 
 
Xg 
X 
 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs + body weight (+ height on 
Day 1 only) 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Physical Examination 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
12- lead ECG (triplicate) 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
MRI (liver/spleen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Echocardiography 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Urinalysisb 
X 
Xe 
 
X 
X 
 
Xe 
Xe 
 
Xe 
Xe 
Xe 
Xe 
 
Xe 
Xe 
Xe 
Blood Draw (Fasting)b 
Chemistry Panel 
X 
X 
 
X 
X 
 
X 
Xg 
 
X 
Xg 
X 
Xg 
 
X 
Xg 
X 
CBC with Differential 
X 
X 
 
X 
X 
 
X 
Xg 
 
X 
Xg 
X 
Xg 
 
X 
Xg 
X 
Serum Lipid Panel 
X 
X 
 
X 
X 
Xg 
X 
 
Xg 
X 
 
X 
 
Xg 
X 
 
X 
Coagulation (aPTT, PT, INR) 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
hsCRP, HbA1c, FPG 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Sedimentation Rate 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Complement (C5a, Bb) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Plasma PK - Volanesorsen 
 
Xh 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Anti-Volanesorsen Antibodies 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
FSH (women only, if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testc 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Archived Serum & Plasma 
Samplesf 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
X 


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Appendix A Schedule of Procedures Continued 
Study Period 
 
Quala 
Treatment Period 
Post Treatment 
Follow-up 
Study Week 
-2 to -1 
Wk 
1 
Wk 
4 
Wk 
8 
Month 3 
Wk 
19 
Month 6 
Wk 
32 
Wk 
38 
Wk 
44 
Month 12 
Wk 
58 
Wk 
65 
Wk 
12 
Wk 
13 
Wk 
25 
Wk 
26 
Wk 
51 
Wk 52 
or ET 
Study Day 
-14 to -7 
1 
2 
22 
50 
78 
85 127 169 176 
218 
260 
302 
351 
358 
400 
449 
Visit Window+/- Days 
0 
0 
0 
2 
2 
2 
2 
3 
2 
2 
3 
3 
3 
2 
2 
7 
7 
Weekly Study Drug: SC Injection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Symptom Diary (weekly) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Food/Drink Diary (quarterly)i 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Quality of Life Assessment(s) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Diet/Alcohol Counselingd 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Adverse Events 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Concomitant Medication  
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
a 
Qualification procedures performed and the patient continues the symptom diary.  Assessments from the Week 52 visit of the index study may be used for 
qualification purposes 
b 
Blood samples to be collected after an overnight fast of at least 10 hours.  During treatment period urine and blood samples will be collected prior to study 
drug administration.  Does not apply to 24 hour PK blood draw 
c 
Females of childbearing potential only 
d 
To reinforce compliance to the diet and alcohol restrictions 
e 
Expanded urinalysis (see Appendix B) 
f 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or adverse events (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of  
volanesorsen 
g 
To be collected by either a clinical service, or Study Center as arranged by the Study Center personnel 
h 
Full or abbreviated PK profile (see Appendix C) 
i 
In addition to diary, patients will be contacted at random times during the study to review their current eating and drinking habits 
 
 


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56 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 304804-CS7 
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57 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of volanesorsen or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL-C 
• 
HDL-C 
• 
Triglycerides 
• 
Non-HDL-C 
• 
VLDL-C 
• 
apoA-1 
• 
apoB 
• 
apoC-III 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1  
& Immunogenicity 
• 
Volanesorsen levels in 
plasma 
• 
Anti-volanesorsen 
antibodies in plasma 
 
Other assessments 
• 
hsCRP 
• 
Sedimentation Rate 
• 
C5a, Bb 
• 
De-lipidated free 
glycerol 
• 
HbA1c, FPG 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
Additional Measures for 
Expanded Urinalysis 
• 
Total protein 
(quantitative) 
• 
Microalbumin 
• 
β2-microglobulin 
 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes of IM assay 
development and/or validation), or to assess other actions of volanesorsen with plasma constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 


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58 
 
 
 
 
 
 
 
Appendix C 
Pharmacokinetic Sampling Schedule 
 
 


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59 
Appendix C Pharmacokinetic Sampling Schedule 
Blood samples for the determination of plasma volanesorsen concentrations will be collected 
prior to dosing, and at various times throughout the dosing and post-treatment follow-up period 
as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional. 
 
 
 


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Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010 
 
 
 


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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 


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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 

SAP_001.pdf: 
Official Title:        
NCT Number: 
Document Date: 
ISIS 304801-CS7 The APPROACH Open Label Study Volanesorsen (ISIS 
304801) An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients With Familial Chylomicronemia Syndrome 
(FCS)
NCT02658175
SAP Version 3.0: 28 March 2019


Statistical Analysis Plan 
ISIS 304801-CS7 
The APPROACH Open-Label Study 
An Open-Label Study of Volanesorsen Administered 
Subcutaneously to Patients with Familial Chylomicronemia 
Syndrome (FCS)  
Date:  28 March 2019 
Version:  3.0


Akcea Therapeutics, Inc. 
SAP 3.0 
CONFIDENTIAL 
Statistical Analysis Plan Signature Page 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, ,9th Floor 
Boston, MA 02210 
Compound Name: 
Volanesorsen (formerly ISIS 304801) 
Protocol: 
ISIS 304801-CS7 
28 MAR2019 
ISIS 304801-CS7 
Study Title: 
An Open-Label Study of Volanesorsen Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
Protocol Issue Date: 
Protocol Amendment 8 - 21 November 2018; 
Protocol Amendment 9 - France - 25 May 2018 
Signature: 
_____ Date: J°/ MAf?. lo// 
Signature: 
 M.D., M.S. 
 
lonis Pharmaceuticals, Inc. 
---~
_____ Date: 
Ph.D. 
lonis Pharmaceuticals, Inc. 
iii 


Akcea Therapeutics, Inc. 
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Signature: 
 
lonis Pharmaceuticals, Inc. 
 
lonis Pharmaceuticals, Inc. 
___ ______________ _ _ 
Date: 
 Ph.D. 
 
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Signature: ______ ___________
_ Date: _____ _ 
Signature: 
 Ph.D. 
 
lonis Pharmaceuticals, Inc . 
-
------
 Ph.D. 
 
Akcea Therapeutics, Inc. 
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Date: 2-1 l'I\.N( -µ;>/ I 


Akcea Therapeutics, Inc. 
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v 
PAREXEL SIGNATURE PAGE 
 
This document has been signed electronically on the final page by the following: 
 
 
 
Signatory 
Author 
 
Project Role: 
 
Biostatistics Reviewer 
 
Project Role: 
 
Statistical Programming 
Reviewer 
 
Project Role: 
 
 
 
 


Table of Contents 
SUMMARY OF CHANGES ................................................................................................................ 1 
Abbreviations ................................................................................................................................ 6 
1 
Introduction ........................................................................................................................... 8 
1.1 
Study Overview ............................................................................................................. 8 
1.2 
Objectives ..................................................................................................................... 9 
1.3 
Hypotheses ................................................................................................................... 9 
1.4 
Endpoints ...................................................................................................................... 9 
1.4.1 
Efficacy Endpoints ........................................................................................................................... 9 
1.4.2 
Safety Endpoints ............................................................................................................................. 9 
2 
Procedures .......................................................................................................................... 11 
2.1 
General Overview of Procedures ................................................................................. 11 
2.1.1 
Screening/Qualification ................................................................................................................ 11 
2.1.2 
Treatment Period .......................................................................................................................... 11 
2.1.3 
Extended Treatment Period ......................................................................................................... 12 
2.1.4 
Pharmacokinetic (PK) Subgroup ................................................................................................... 13 
2.1.5 
Post-Treatment Period ................................................................................................................. 13 
2.2 
Randomization & Treatment Allocation ....................................................................... 13 
2.3 
Conduct ....................................................................................................................... 14 
2.4 
Data Monitoring .......................................................................................................... 14 
2.4.1 
Safety Data Monitoring ................................................................................................................ 14 
2.4.2 
Data Monitoring Board ................................................................................................................. 14 
2.5 
Data Management ....................................................................................................... 14 
2.5.1 
Case Report Form (CRF) Data ....................................................................................................... 14 
2.5.2 
Laboratory Data ............................................................................................................................ 15 
2.5.3 
Pharmacokinetics (PK) Data .......................................................................................................... 15 
2.5.4 
Other Data .................................................................................................................................... 15 
2.5.5  
Adverse Events Adjudication ........................................................................................................ 15 
3 
Analysis Plan ....................................................................................................................... 16 
3.1 
Statistical Design Summary ......................................................................................... 16 


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3.1.2 
Sample Size Consideration ............................................................................................................ 16 
3.1.3 
Planned Interim Analysis .............................................................................................................. 16 
3.2 
General Overview of Analyses ..................................................................................... 16 
3.2.1 
Statistical Methods ....................................................................................................................... 16 
3.2.2 
Patient Population Analyzed ........................................................................................................ 19 
3.2.3 
Baselines and Other Definition ..................................................................................................... 19 
3.2.4 
Patient Baseline data, Medical history and Disposition ............................................................... 21 
3.3 
Efficacy Analysis .......................................................................................................... 22 
3.3.2 
Percent change and absolute change from baseline in fasting TG ............................................... 23 
3.3.3 
Treatment response rates ............................................................................................................ 24 
3.3.4 
Incremental effects of volanesorsen on lipid measures ............................................................... 24 
3.3.5 
Frequency and severity of patient reported abdominal pain ....................................................... 25 
3.3.6 
Percent change and change from baseline in other fasting lipid measurements ........................ 25 
3.3.7 
Percent change and change from baseline in fasting total apoC-III ............................................. 26 
3.3.8 
Change from baseline in Quality of Life (QOL) questionnaires (EQ-5D, SF-36) ............................ 26 
3.3.9 
Adjudicated acute pancreatitis events Rate ................................................................................. 26 
3.3.10 
Frequency of other symptoms: eruptive xanthoma, lipemia retinalis .................................... 27 
3.4 
Pharmacokinetic and Immunogenicity Analysis ........................................................... 27 
3.4.1 
Pharmacokinetic Analysis ............................................................................................................. 27 
3.4.2 
Immunogenicity (IM) Analysis ...................................................................................................... 29 
3.5 
Safety Analyses ........................................................................................................... 30 
3.5.2 
Adverse Events ............................................................................................................................. 32 
3.5.2.1 General Analysis of AEs ................................................................................................................... 32 
3.5.2.2 
Adverse Events of Special Interest ........................................................................................... 34 
3.5.2.3 
Other Events of Interest ........................................................................................................... 34 
3.5.3 
Vital Signs Measurements ............................................................................................................ 36 
3.5.4 
Laboratory Measurements ........................................................................................................... 36 
3.5.4.1 
 General analysis of safety laboratory data ............................................................................. 36 
3.5.4.2 
Additional analyses of key safety laboratory data ................................................................... 37 
3.5.5 
Exposure ....................................................................................................................................... 41 


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3.5.6 
Physical Examination .................................................................................................................... 42 
3.5.7 
12-Lead Electrocardiogram ........................................................................................................... 42 
3.5.8 
Echocardiogram ............................................................................................................................ 42 
3.5.9 
Concomitant Medications ............................................................................................................ 42 
3.5.10 
MRIs ......................................................................................................................................... 43 
4 
Bibliography ........................................................................................................................ 44 


Akcea Therapeutics, Inc. 
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28 MAR 2019 
SAP 3.0 
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1 
SUMMARY OF CHANGES 
The following major modifications have been made to ISIS 304801 CS7 SAP, version 3.0, dated 25 
MAR 2019. 
List of Modifications 
Section 
Title 
Change/Rationale 
2.1 
General Overview of 
Procedures 
Add extended treatment period 
3.2.1 
Statistical Methods 
Change Study Day Window for Abdominal Pain screening 
period from “Screening” to “Week -1”, “Week “-2”, etc. 
Correct  Abdominal Pain Week 1 study day window from "1" 
to "1 to - 3";  
Add MRI mapped visits and study day windows 
Add patient year of exposure as used in AdHoc analysis  
Update Study Day Window for Fasting Lipid Assessment 
Week 52 and Week 64 to be taking the midpoint of next 
visit which is consistent with visit windows for other visits. 
Add Study Day Window week 78, 117, 130 for Quality of Life 
Assessments (EQ-5D, SF-36) – France per protocol 
Amendment 9 -France 
Add fasting lipid assessment week 117 and week 130 
(France) study day window 
3.2.2 
Patient Population Analyzed 
Removed per-protocol set. The first 13 week dosing 
compliance will not bring much value for the long term 
efficacy in this long-term extension open label study. 
3.2.3 
Baselines and Other 
Definition 
QOL: remove “Pre-dose” from definition  
12-lead ECG: Remove “(4 weeks)” from definition 
MRI: clarify MRI baseline definition as “last non-missing 
assessment on or prior to Study Day 14 of volanesorsen in 
index studies or Open-label study”  
3.2.4 
Patient Baseline data, 
Medical history and 
Disposition 
Add description of AdHoc summaries: 
• 
Disposition through Studies CS6 and CS7 
• 
Disposition/number of patients by month through 
index and open-label study 
• 
Discontinuation Rate in the index studies and 
open-label study overall 
• 
Kaplan Meier Plot of Treatment Continuation 


Akcea Therapeutics, Inc. 
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Section 
Title 
Change/Rationale 
3.3 
Efficacy Analysis 
Add description of AdHoc summaries:  
• 
Summary and by patient listing of dosing, TG, 
platelet, pancreatitis, and abdominal pain 
• 
By age group summaries  
• 
Pancreatitis incidence rate per patient year 
3.3.5 
Frequency and severity of 
patient reported 
abdominal pain 
Change “treatment period” to “on-treatment period” 
Add description of AdHoc summaries: 
• 
Summary for CS6 subjects who roll-over to CS7 
• 
Summary and figure for patients with pain at 
baseline in CS6 subjects who roll-over to CS7 
• 
Patient profile figures 
3.3.9 
Adjudicated acute 
pancreatitis events Rate 
Add patient reported moderate or severe abdominal pain 
(pain score:  4-10) in the planned summary.  
Add description of AdHoc summaries: pancreatitis incidence 
rate per patient year of exposure 
3.5 
Safety Analyses 
On-Study period was updated from “the first dose of the 
Study Drug to end of the study” to “Day 1 of volanesorsen 
to end of the study” 
On-treatment period was updated from “the first dose of 
the study medication to the last dose of study medication + 
28 days.” to “the first dose of volanesorsen to the last dose 
of volanesorsen + 28 days.” 
3.5.2.1 
General Analysis of AEs 
Add description of AdHoc summaries: 
1. Summary of on-study AEs by treatment and age for FCS 
patients and all patients in safety set 
2. Summary of treatment emergent renal adverse events 
3.5.2.3 
Other Events of Interest 
Add description of Platelet Count Decreased/ 
Thrombocytopenia Events from AdHoc summary 
Add below description of additional analysis in AdHoc 
request: 
“The frequency of patients with any incidence of AEs and 
the number of events will be summarized by MedDRA 
preferred term (and severity) sorted by frequency for: 
1. Any treatment emergent bleeding AEs for the safety 
set, for the subset of patients on concomitant anti-
coagulant or anti-platelet medication, and for the 
subset of patients not on concomitant anti-
coagulant or anti-platelet medication. 
2. Treatment emergent bleeding AEs under 


Akcea Therapeutics, Inc. 
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28 MAR 2019 
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Section 
Title 
Change/Rationale 
contemporaneous use of concomitant anti-
coagulant or anti-platelet medication for the 
subset of patients on concomitant anti-coagulant 
or anti-platelet medication. 
Treatment emergent bleeding adverse events will be listed. 
In addition, treatment emergent bleeding adverse events 
will be listed by platelet count categories before and after 
bleeding, and anti-platelet or anti-coagulant medication.” 
Add description of additional analysis in post-submission 
request: 
1. Revised LCRIS  
2. Discoloration AE 
Add Revised FLRs definition  
3.5.4.2 
Additional analyses of key 
safety laboratory data 
Add below description of additional analysis in AdHoc 
request: 
“The incidence of patients with post-baseline platelet 
results falling in each of the following categories will be 
summarized for the safety set and the subset of patients 
with normal baseline (≥140,000/mm3): 
• 
With >= 2 consecutive values of platelet count < 
140,000/mm3 
• 
With platelet count <100,000/mm3 at final visit 
• 
With >= 2 consecutive values of platelet count < 
140,000/mm3 or with platelet count <100,000/mm3 at 
final visit 
 
Summary figures will be generated for platelet counts over 
time (absolute values, absolute change from baseline, and 
percent change from baseline) in patients treated with 
placebo in ISIS 304801-CS6 who then treated with 
Volanesorsen in ISIS 304801-CS7. 
The incidence of patients with post-baseline platelet results 
falling in each of the following categories will be 
summarized for the safety set: 
• 
Any serum creatinine >=0.3 mg/dL higher than 
baseline  
• 
Any serum creatinine >=50% higher than baseline 
• 
Final visit serum creatinine >=0.3 mg/dL higher 
than baseline  
• 
Final visit serum creatinine >=50% higher than 


Akcea Therapeutics, Inc. 
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28 MAR 2019 
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Section 
Title 
Change/Rationale 
baseline” 
Add below description of additional analysis in post-
submission request: 
“hsCRP will be classified to Normal or > Upper limit of 
normal (ULN), and the incidence rate of shift from safety 
baseline to maximum post-baseline category will be 
summarized.” 
Add coagulation assessments shift table based on the 
toxicity grade 
Add summary of platelet count (any occurrence/nadir 
value) 
Add ratio of post-baseline central (and local) lab platelet 
test numbers to total number of injections 
Add time to recover from platelet values 
Add summary figure (overall and by age group) for platelet 
count over time 
Add scatter plot for nadir platelet counts vs. selected factors 
Add summary table and figure of selected 
hematology/urinalysis/normalized urinary creatinine 
assessments 
Add shift tables for urine albumin/creatinine ratio and urine 
protein/creatinine ratio 
Add listing for patients with ALT or AST > 3 x ULN 
3.5.5 
Exposure 
Updated to add dose adjustment, dose interruption/pauses; 
and remove amount of Study Drug in mg from the 
description of exposure summaries 
Add treatment duration in months during index study and 
open-label study description per request in post-
submission. 
Add summary of dose interruption/reduction, number of 
dose pauses and missed dose per patient year of exposure. 


Akcea Therapeutics, Inc. 
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Section 
Title 
Change/Rationale 
3.5.9 
Concomitant Medications 
Update WHODrug version from Dec 2014 to Sep 2016;  
Add below description of additional analysis in AdHoc 
request: 
“Concomitant anti-coagulant and anti-platelet medications 
will also be summarized for the Safety Set by decreasing 
frequency in the overall column.” 


Akcea Therapeutics, Inc. 
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6 
ABBREVIATIONS 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALP 
Alanine Phosphatase 
ALT 
Alanine Aminotransferase 
apo 
Apolipoprotein  
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
Cmax 
Maximum Observed Drug Concentration 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ET 
Early Termination 
FAS 
Full Analysis Set 
FCS 
Familial Chylomicronemia Syndrome 
FLRs 
Flu-like Reactions  
GLP-1 
Glucagon-like Peptide-1 
GPIHBP1 
Glycosylphosphatidylinositol-anchored HDL-binding Protein 1 
HbA1c 
Glycated Hemoglobin 
HDL 
High-Density Lipoprotein 
HDL-C 
High-Density Lipoprotein Cholesterol 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IM 
Immunogenicity 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LCRIS 
Local Cutaneous Reaction at Injection Site 
LDL 
Low-Density Lipoprotein 
LDL-C 
Low-Density Lipoprotein Cholesterol 


Akcea Therapeutics, Inc. 
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LMF1 
Lipase Maturation Factor 1 
LPL 
Lipoprotein Lipase 
MACE 
Major Acute Cardiovascular Event 
MCMC 
Markov Chain Monte Carlo 
MMRM 
Mixed Model for Repeated Measures 
MRT 
Mean Residence Time 
non-HDL-C 
Non-High-Density Lipoprotein-Cholesterol 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time to Maximal Concentration 
TG 
Triglyceride 
ULN 
Upper Limit of Normality 
VLDL 
Very-Low-Density Lipoprotein 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
28 MAR 2019 
SAP 3.0 
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8 
1 
INTRODUCTION 
This document provides a description of the statistical methods and procedures to be implemented 
for the analyses of data from the Akcea Therapeutics, Inc. study with protocol number ISIS 304801-
CS7.  Section 1 discusses study design, objectives, and endpoints; Section 2 provides the study 
procedures; and, Section 3 provides the detailed plan for the statistical analyses. 
Any deviation from the final version of the Statistical Analysis Plan will be substantiated by sound 
statistical rationale and will be documented in the final clinical study report. 
1.1 
Study Overview 
This is an open-label study of: 
Group 1: ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2: ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3: FCS patients who did not participate in the ISIS 304801-CS6 or ISIS 304801-CS16 index 
studies. 
Up to approximately 70 patients will receive 300 mg once weekly volanesorsen for 52 weeks in the 
CS7 study.  
Following the Week 52 visit, patients will have the option of participating in an expanded access 
program or continuing dosing for up to an additional 52 weeks until an expanded access program is 
approved and available in their country. Patients not participating in an expanded access program 
will enter a 13-week post-treatment evaluation period. 
There is no primary efficacy endpoint. Both efficacy endpoints and safety endpoints will be 
summarized to evaluate the safety and efficacy of extended dosing with volanesorsen sodium 300 
mg in patients with FCS.  
Groups 1 and 2 (Qualification):  During the qualification period, the eligibility of the patient to enroll 
in the open-label study will be determined. Final assessments from the ISIS 304801-CS6 or ISIS 
304801-CS16 studies may be used for qualification. A period of up to 2 weeks after completion of 
the ISIS 304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given to 
complete qualification. Qualified patients will retain the unique patient identification number that 
was assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.  
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered 
enrolled into the study and will be assigned a unique screening number before any study 
procedures, including screening procedures, are performed.   
Patients will be enrolled into the treatment phase of the study after all Screening (Group 3) and 
qualification assessments have been completed and after the Investigator has verified that they are 
eligible per criteria in protocol Sections 5.1 and 5.2.  No patient may begin treatment prior to 
enrollment. 


Akcea Therapeutics, Inc. 
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1.2 
Objectives 
To evaluate the safety and efficacy of dosing and extended dosing with ISIS 304801 (volanesorsen 
sodium 300 mg) in patients with FCS. 
1.3 
Hypotheses 
There is no formal study hypothesis. Hypothesis tests for efficacy endpoints will be done for 
exploratory purposes. 
1.4 
Endpoints 
For fasting lipid measurements including TG, total cholesterol, non-HDL-C, apoB, HDL-C, 
apolipoprotein A-1 (apoA-1), VLDL-C, LDL-C, and total apolipoprotein C-III :  
The values at Month 3 analysis time point are defined as the average of Week 12 (Day 78) and 
Week 13 (Day 85) fasting assessments,  
The values of Month 6 analysis time point is at the end of Month 6 are defined as the average 
of Week 25 (Day 169) and Week 26 (Day 176) fasting assessments, and  
The values at the Month 12 analysis time point are defined as the average of Week 50 (Day 
344) and Week 52 (Day 358) fasting assessments.  
1.4.1 
Efficacy Endpoints  
• 
Percent change and absolute change from baseline in fasting TG,  
• 
Frequency and severity of patient reported abdominal pain during the on-treatment period, 
• 
Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C, 
• 
Percent change from baseline in fasting total apolipoprotein C-III,  
• 
Change from baseline in Quality of Life (QOL) questionnaires (EQ-5D, SF-36),  
• 
Independently adjudicated acute pancreatitis event rate,  
• 
Frequency of other symptoms: eruptive xanthoma, lipemia retinalis.  
1.4.2 
Safety Endpoints  
• 
Number and percentage of patients reporting AEs including independently adjudicated 
events of pancreatitis and major acute cardiovascular events (MACE), local cutaneous 
reactions at injection site, flu-like reactions, and platelet reduction,  
• 
Change from baseline in vital signs and weight, 
• 
Change in physical examinations findings, 


Akcea Therapeutics, Inc. 
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• 
Change from baseline in clinical laboratory tests (serum chemistry, hematology, coagulation, 
urinalysis), 
• 
Chang in echocardiography findings, 
• 
12-Lead electrocardiograms (ECGs) results, 
• 
Use of concomitant medications, and 
• 
Change from baseline in MRIs. 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
28 MAR 2019 
SAP 3.0 
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11 
2 
PROCEDURES 
The study for an individual patient will generally consist of the following periods: 
• 
Screening/Qualification: 
• 
Qualification of Group 1 and 2 patients (participated in ISIS 304801-CS6 or ISIS 304801-CS16 
index study): A qualification period of up to 2 weeks (unless approved by the Sponsor).  
• 
Screening and Qualification of Group 3 patients (did not participate in an index study): An up 
to 8-week screening and qualification period, including a diet stabilization period of at least 
6 weeks.  
• 
A 52-week treatment period during which volanesorsen will be administered as a once 
weekly SC injection 
• 
Option to participate in an extended treatment period (up to an additional 52 weeks) 
• 
A 13-week post-treatment evaluation period 
2.1 
General Overview of Procedures 
2.1.1 
Screening/Qualification  
Group 1 and 2 patients (Qualification): During the qualification period, the eligibility of the patient to 
enroll in the open-label study will be determined.  Final assessments from the ISIS 304801-CS6 or 
ISIS 304801-CS16 studies may be used for qualification.  A period of up to 2 weeks after completion 
of the ISIS 304801-CS6 or ISIS 304801-CS16 index studies (unless approved by the Sponsor) is given 
to complete qualification.  Qualified patients will retain the unique patient identification number 
that was assigned to them during the ISIS 304801-CS6 or ISIS 304801-CS16 index studies.   
Group 3 (Screening and Qualification):  At the time of consent, the patient will be considered 
enrolled into the study and will be assigned a unique screening number before any study 
procedures, including screening procedures, are performed.  At the time of enrollment, patients will 
be assigned a unique patient identification number.  This number will be used to identify the patient 
throughout the trial and must be used on all study documentation related to that patient.  In the 
event the patient is re-consented and re-screened the patient must be given a new screening 
number.  Screening numbers and patient identification numbers, once assigned, will not be re-used. 
2.1.2 
Treatment Period 
The patients, Investigators, study staff, and the Sponsor will remain blinded to lipid data through the 
last patient’s Week 13 visit of the open-label study or until results from the database locks for the 
ISIS 304801-CS6 and ISIS 304801-CS16 index studies become available, whichever comes first. 
During the treatment period, patients will report to the study center for clinic visits a minimum of 10 
times during Weeks 1-52 (see Schedule of Procedures in Appendix A of the protocol).  Study Drug 
will be administered once weekly unless the patient is on a biweekly dosing schedule for safety 


Akcea Therapeutics, Inc. 
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reasons.  Collection and measurement of vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, and urinalysis), AEs, concomitant medication/procedure information, 
lipid panel, volanesorsen plasma trough concentrations, immunogenicity (IM) testing, liver/spleen 
MRI, ECGs, echocardiograms and QOL assessments will be performed according to the schedule of 
procedures in Appendix A of the protocol.  AEs at the injection site should be collected as AEs.  
Dietary counseling will commence at the start of the diet stabilization period and will be reinforced 
at intervals throughout the treatment and follow-up period.  All blood and urine samples should be 
collected prior to Study Drug administration.  Blood sampling at Weeks 2.5, 4, 6, 8, 10, 12, 15, 17, 
19, 21, 23,  25, 28, 30, 32, 34, 36, 40, 42 44, 46, 48,  and 50 may be conducted by a home healthcare 
nurse .  Approval for study procedures to be conducted by a home healthcare nurse on other 
outpatient visit days will require prior approval by the Sponsor.  Patients must be fasted prior to 
drawing all blood samples and samples drawn locally should also be sent to the central laboratory 
for analysis whenever possible.  Every effort should be made to ensure the previous week’s dose is 
given 7 days prior to a scheduled clinic visit.  Dosing instructions and training will be provided to the 
patient where applicable. 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined in 
Appendix A of the protocol.  However, in the event that a visit does not occur or is delayed, all 
subsequent visits should be calculated based on the time elapsed since Day 1 rather than from the 
date of the previous visit.  
Any patient who discontinues early from the Treatment Period should be followed as per the 
platelet monitoring rules shown in Section 8.6.3 of the protocol for the first 6 weeks after 
discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 3 consecutive 
values that are stable as determined by the Sponsor Medical Monitor and > 100,000/mm3), the next 
platelet count should be taken within at least 6 weeks so that patients are monitored for at least 12 
weeks after discontinuing Study Drug.  Patients should also be strongly encouraged to attend 
applicable landmark visits at Weeks 12, 13, 25, 26, and 50, 52 (calculated based on the time elapsed 
since Day 1) to collect fasting lipid panels and conduct safety assessments in accordance with the 
Schedule of Procedures.  Any patient who discontinues treatment after Week 44 should also be 
strongly encouraged to attend a final follow-up visit (Week 65 visit assessments) approximately 13 
weeks after their last dose of Study Drug, in addition to the applicable landmark visits. 
2.1.3 
Extended Treatment Period 
Patients will have the option of continuing treatment for up to an additional 52 weeks until an 
expanded access program is approved and available in their country. 
During the extended treatment period, patients will report to the study center for clinic visits during 
Weeks 54-104 (see Schedule of Procedures in Appendix A of the protocol).  Study Drug will be 
administered once weekly unless the patient is on a biweekly treatment schedule for safety reasons.  
Collection and measurement of vital signs, clinical laboratory parameters (including hematology, 
serum chemistry, and urinalysis), AEs, concomitant medication/procedure information, lipid panel, 
volanesorsen plasma concentrations, IM testing, ECGs, and physical examinations will be performed 
according to the Schedule of Procedures in Appendix A.  Adverse events at the injection site should 


Akcea Therapeutics, Inc. 
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13 
be collected as adverse events.  Dietary counseling will be reinforced at intervals throughout the 
extended treatment period.  All blood and urine samples should be collected prior to volanesorsen 
administration.  Blood sampling at Weeks 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 65, 66, 67, 68, 69, 
70, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 94, 95, 96, 97, 98, 
99, 100, 101, 102, and 103 may be conducted by a home healthcare nurse.  Approval for study 
procedures to be conducted by a home healthcare nurse on other outpatient visit days will require 
prior approval by the Sponsor.  Patients must be fasted prior to drawing all blood samples and 
samples drawn locally should also be sent to the central laboratory for analysis whenever possible.  
Treatment instructions and training will be provided to the patient where applicable. 
2.1.4 
Pharmacokinetic (PK) Subgroup 
A subgroup of patients will participate in an extended PK collection.  Patients in this subgroup will 
have more frequent PK sampling over a 24-hour period following the first dose on Study Day 1 in 
order to evaluate the plasma PK parameters of volanesorsen.  Patients in this subgroup will have an 
additional visit to the clinic, or by a home healthcare nurse, on Day 2 to collect a 24-hour post-dose 
blood draw after dosing on Day 1.  The detailed PK sampling schedules are outlined in Appendix C of 
the protocol. 
Participation in the PK subgroup is optional for sites and patients, and consent may be withdrawn 
for the subgroup-specific procedures (e.g., multiple blood draws for PK) without being withdrawn 
from the study.  If a patient withdraws consent from the subgroup procedures, he/she should 
remain on study and continue to follow all the non-subgroup assessments and procedures as 
outlined in Appendix A of the protocol. 
2.1.5 
Post-Treatment Period 
After completion of the Week 52 visit assessments, patients will have the option of participating in 
an expanded access program or continuing dosing for up to an additional 52 weeks until an 
expanded access program is approved and available in their country. Patients not participating in an 
expanded access program will enter the 13-week post-treatment evaluation period. This 13-week 
post-treatment evaluation period consists of 4 Study Center visits on Weeks 54, 56, and 58 (which 
may be conducted by a home healthcare nurse), and Week 65 as outlined in the Schedule of 
Procedures in Appendix A of the protocol. Patients who complete, or terminate early from, the 
extended treatment period without subsequently participating in an expanded access program will 
enter a 13-week post-treatment evaluation period consisting of 4 Study Center visits on Weeks 106, 
108, and 110 (which may be conducted by a home healthcare nurse), and Week 117 as outlined in 
the Schedule of Procedures in Appendix A of the protocol.  
2.2 
Randomization & Treatment Allocation 
This is an open-label study to the Phase 3 study of rolled over volanesorsen patients with FCS (ISIS 
304801-CS6 or ISIS 304801-CS16) and newly-enrolled patients who did not participate in the index 
studies. All patients will initiate treatment with volanesorsen 300mg by SC injection weekly and 
continue on this dose and regimen unless they meet a per-protocol dose adjustment criterion.  


Akcea Therapeutics, Inc. 
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2.3 
Conduct 
The study will be conducted in accordance with current Good Clinical Practice and International 
Conference on Harmonization (ICH) guidelines, the World Medical Association Declaration of 
Helsinki guidelines, the Food and Drug Agency (FDA) Code of Federal Regulations, and all other local 
regulatory requirements. 
2.4 
Data Monitoring 
2.4.1 
Safety Data Monitoring 
The Sponsor (or designee) is responsible for processing all reported AEs.  Processing of serious 
adverse events (SAEs) is delegated to a CRO although the Sponsor remains accountable for this 
activity and process. AEs and SAEs are reviewed according to standard operating procedures.  The 
Sponsor medical monitor will review all AEs and SAEs on an ongoing basis throughout the study.  
The Sponsor (or designee) will prepare and submit safety reports to the health authorities 
worldwide in accordance with local requirements.  If it becomes necessary to communicate new 
safety information, the Sponsor (or designee) will also prepare a safety notification letter and 
transmit it to all applicable study sites. 
2.4.2 
Data Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be assembled to review safety, 
tolerability and efficacy (as needed) data collected on volanesorsen during this study.  Based on its 
ongoing assessment of the safety and tolerability of volanesorsen, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review, meeting schedules and controlled access to 
unblinded data are outlined in the DSMB Charter. 
In order to ensure maintenance of the study blind before index study completion, lipid panel results, 
including apoC-III, will not be available to the Sponsor, monitors, Investigators, Study Center 
personnel, or the patients, except for the procedure related to safety monitoring for LDL-C 
elevations as specified in protocol section 8.5.5. 
For the purpose of pre-programming and data cleaning, PAREXEL unblind programming team (the 
CRO performing the statistical analysis) and an independent data manager at Medpace Laboratories 
will receive post-baseline lipid panel results. 
2.5 
Data Management 
The following is applied to all index studies (ISIS 304801-CS6 or ISIS 304801-CS16) and all 3 groups in 
this open-label study. 
2.5.1 
Case Report Form (CRF) Data 
BioClinica® is responsible for creating the Electronic Data Capture (EDC) data entry screens, 
database and edit checks using definitions developed by the Sponsor.  The Sponsor is responsible for 
the review, data management querying and locking of the database. 


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Data are single-entered into the EDC system by the investigator site staff.  Programmed edit checks 
(computer logic that checks the validity of the data entered and also prompts for missing data that is 
expected to be entered) are run and automatic queries are generated. The Sponsor performs 
blinded review of all data for accuracy and validity; generating additional queries in the EDC system 
when necessary.  The data is corrected or an explanation concerning the query is provided in the 
EDC system.  After all data is entered, reviewed, source data verified and all queries are resolved the 
database will be locked. 
2.5.2 
Laboratory Data 
The Sponsor is responsible for the format of the laboratory electronic data transfers and the transfer 
schedule.  The Sponsor is responsible for the review of the clinical laboratory data.  This data is not 
stored in the EDC system.  Investigator sites have access to the data via printed lab reports sent 
directly from the laboratory.  
2.5.3 
Pharmacokinetics (PK) Data 
The Sponsor is responsible for the management and review of the PK data. This process involves 
reviewing the patient and visit identifiers with the clinical data collected in the EDC system. The PK 
data are not stored in the EDC system. 
2.5.4 
Other Data 
Bracket is the eDiary vendor that contains abdominal pain and QoL assessments.  Medpace Imaging 
Central Lab manages MRI, ECHO, and Fundus photography. Blood Center of Wisconsin manages 
antiplatelet antibodies and anti-PF4 assay data. Quest Pharmaceutical Service manages anti-
volanesorsen antibody assessment. University of Western Ontario (
Professor 
) manages genetic sequencing data. These data will also not be stored in the EDC system but 
will be transferred to the Sponsor as external data. 
2.5.5  Adverse Events Adjudication 
 is the vendor that manages the adjudication process. 
All SAEs that occur during the study that are consistent with MACE will be adjudicated by a blinded, 
independent committee as outlined in the MACE Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute pancreatitis 
will be adjudicated by a blinded, independent committee according to the Atlanta classification of 
acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis Adjudication Charter.  In 
addition, data for prior episodes of acute pancreatitis or suspected pancreatitis will be collected by 
review of each patient’s medical chart and these events will also be independently adjudicated. 
 


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3 
ANALYSIS PLAN 
3.1 
Statistical Design Summary 
This is a multi-center open-label study of: 
Group 1: ISIS 304801-CS6 (index study) roll over FCS patients 
Group 2: ISIS 304801-CS16 (index study) roll over FCS patients 
Group 3: FCS patients who did not participate in the ISIS 304801-CS6 or ISIS 304801-CS16 index 
studies. 
Group 1 and Group 2 patients who complete one of the index studies and who are qualified plus 
Group 3 patients who are screened and qualified will be enrolled to this open-label study. The safety 
and efficacy of extended dosing with volanesorsen in patients with FCS will be evaluated by 
summary tables rather than hypothesis tests. Missing data will not be imputed. 
3.1.2 
Sample Size Consideration 
No sample size calculations were performed as this is an open-label extension study.  
3.1.3 
Planned Interim Analysis 
An interim analysis may be conducted after the last patient’s Week 13 visit of the open-label study 
or after the database of the ISIS 304801-CS6 and ISIS 304801-CS16 index studies are locked and 
unblinded.  
Planned summaries and patient data listings for disposition, demographic, efficacy and safety will be 
included in this interim analysis.  
Additional interim analyses will be performed to support regulatory filing activities. 
3.2 
General Overview of Analyses 
3.2.1 
Statistical Methods 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be provided in 
the patient data listings. Patient data listings will be presented for all patients enrolled into the 
study. Descriptive summary statistics including n, mean, median, standard deviation, standard error, 
interquartile range (25th percentile, 75th percentile), and range (minimum, maximum) for 
continuous variables, and counts and percentages for categorical variables.   
Efficacy data including fasting lipid measurements, abdominal pain and QOL results will be mapped 
to analysis visit specified in the table below.  
The intent of these visit windows is not to align with those prescribed for visit scheduling in the 
clinical study protocol but, rather, based on the protocol-defined target study day, to delineate 
mutually exclusive windows so that all efficacy assessments proximal to a particular study week can 


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be integrated to best represent the patient’s status during that period of the study. If a patient 
discontinued early from the treatment period but attended applicable landmark visits at Weeks 12, 
13, 25 and etc. to collect efficacy assessments, then those assessments collected at Early 
Termination visit and during post-treatment follow-up period should be mapped to analysis visits as 
well. If there are multiple assessments within a visit window, only scheduled visit will be used. If 
there are multiple scheduled assessments, for fasting lipid measurements and numeric QOL results, 
average will be used; for abdominal pain and character QOL results, the worst will be used. If the 
assessments are all unscheduled, the visit nearest the scheduled date will be used unless two visits 
are equally near, in which case the average will be used. For fasting lipid data, local lab data will not 
be used unless central lab assessments are not available at certain visit. When calculating the 
baseline and analysis endpoints, only if the data from central lab is missing, then the local lab data 
will be utilized. 
Efficacy/PD measure 
Mapped Visit (Week) 
Target 
Study Day Window 
Fasting Lipid Assessment 
Screening 
-56 to -15 
≤-15 
 
Qual Visit 
-14 to -7 
-14 to <1 
 
1 
1 
1 
 
4 
22 
2 to 36 
 
8 
50 
37 to 64 
 
12 
78 
65 to 82 
 
13 
85 
83 to 106 
 
25 
169 
107 to 173 
 
26 
176 
174 to 197 
 
38 
260 
198 to 302 
 
50 
344 
303 to 351 
 
52 
358 
352 to 400 
 
extended treatment 
period 
 
 
 
64 
442 
401 to 484 
 
76 
526 
485 to 575 
 
90 
624 
576 to 673 
 
104 
722 
674 to 743 
 
117 
813 
744 to 858 
 
130 (France) 
904 
859 to 949 
Abdominal Pain 
 
m 
n×7+1 
mx7+3 to mx7-3,  
m = -1, -2, … 
 
… 
 
 
 
-2 
-13 
-11 to -17 
 
 -1  
-6 
-4 to -10 
 
1  
1 
1 to -3 
 
2 
8 
5 to 11 


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3 
15 
12 to 18 
 
             n 
(n-1) ×7+1 
(n-1)×7-2 to (n-1) ×7+4 
 
… 
 
 
MRI 
 
Screening 
NA 
≤ 14 
 
52 
358 
298 to 418 
Quality of Life Assessments (EQ-5D, SF-36) 
 
1 
1 
1 
 
13 
85 
55 to 115 
 
26 
176 
146 to 206 
 
52 
358 
328 to 404 
 
65 
449 
405 to 479 
 
78 (France) 
540 
496 to 570 
 
117 (France) 
813 
769 to 843 
 
130 (France) 
904 
860 to 934 
Note: Regarding lipid measurements for efficacy analyses, mapped observed assessments defined in this table 
will be derived further. The derivations for baselines are described in section 3.2.3. The derivations for Month 
3, 6 and 12 are described in section 3.3.1.  
Non-efficacy by visit assessments will be summarized using the visit labels provided in the data.  
Multiple results with the same visit label will be averaged.   
Unscheduled results and data from local labs will not be included in the by visit summaries but will 
be used in the determination of baseline, in the laboratory abnormality, stopping rule, and platelets 
reduction analyses presented in data listings.  
Unscheduled results from the central lab will be used in the determination of baseline, laboratory 
abnormality summaries, and shift from safety baseline to worst post-baseline, and platelets 
reduction analyses only, and presented in data listings. Local lab data will be only used in platelet 
analyses (including by visit summaries, abnormality summary, shift from Baseline to worst post-
baseline, reduction analyses), and presented in data listings. 
Summary tables and figures will NOT be presented by the treatment group in each index study 
(ISIS 304801-CS6 or ISIS 304801-CS16) and the newly enrolled patients as a separate group per 
protocol. Per Sponsor decision, most summary tables and figures will be presented in the following 
groups, i.e. Treatment naive group, CS6-Volanesorsen, CS16-Volanesorsen, and Overall, if applicable.  
Note: “Treatment naive group” for most tables and figures is a combined group of subjects including 
CS7-New, CS6-Placebo and CS16-Placebo. When the summary is based on Index Study Baseline, 
“Treatment naive group” is a combined group of subjects including CS6-Placebo and CS16-Placebo. 
Summary tables for PK concentration and IM data will be presented by Treatment naive group, CS6-
Volanesorsen, CS16-Volanesorsen, and Volanesorsen combined (i.e., CS6-Volanesorsen and 
CS16-Volanesorsen combined). Summary figures for PK concentration data and summary tables for 
PK parameters will be presented by Treatment naive group and Volanesorsen combined. 


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Total patient year of exposure will be calculated as summation of [minimum (latest visit date, data 
cutoff date) – treatment start date +1]/365.25 for all subjects. 
For listings, data will be displayed as an order of following: 
• 
Treatment naive group: CS7-New  
• 
Treatment naive group: CS6-Placebo  
• 
Treatment naive group: CS16-Placebo  
• 
CS6-Volanesorsen  
• 
CS16-Volanesorsen  
3.2.2 
Patient Population Analyzed 
The following analysis populations will be used for the analysis of data as described within each 
analysis set. 
Full Analysis Set (FAS):  All patients who are enrolled and received at least one dose of Study Drug 
and who have an open-label study baseline TG assessment.  The FAS represents the practically-
feasible intent-to-treat (ITT) population as delineated in ICH Guideline E9.  
The significant deviation criteria are listed in Appendix A. 
All protocol deviations will be listed in the patient data listings. 
Safety Set:  All patients who are enrolled and receive at least one dose of Study Drug. Group 1 and 
Group 2 patients will be summarized in the actual treatment group patients received during index 
study. Patients randomized to receive placebo in the index study, incorrectly treated with 
volanesorsen during the index study treatment period will be counted in the volanesorsen group 
from the first dose of volanesorsen received.  
PK Population: All patients who are enrolled and receive at least one dose of Study Drug, and have 
at least one post first dose PK sample collected, analyzed, and not excluded by PK scientist as the PK 
result was considered to be an outlier. Group 1 and Group 2 patients will be summarized in the 
actual treatment group patients received during index study. Patients randomized to receive 
placebo in the index study, incorrectly treated with volanesorsen during the index study treatment 
period will be counted in the volanesorsen group from the first dose of volanesorsen received. 
Group 3 patients will be summarized under Treatment naive group. 
All efficacy endpoints will be assessed in the FAS. All safety assessments will be performed on the 
Safety Set. PK endpoints will be assessed in the PK Set as applicable.  
Analysis populations will be summarized with counts and percentages by the group presented in 
Section 3.2.1.  
3.2.3 
Baselines and Other Definition 
Baselines for fasting lipid measurement:  


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Definitions of baselines, including the Index Study Baseline (for Group 1 and Group 2 only) and the 
Open-label Study Baseline (for Group 1, 2, and 3) , are given below for the purposes of the final 
analysis.  
• 
Index Study Baseline for Group 1 and 2 is defined as the average of Index Study Day 1 pre-
dose assessment and the last measurement prior to Index Study Day 1 pre-dose assessment.  
If one of the two measurements is missing, then the other measurement will be assigned as 
the baseline value.  If both are missing, then the baseline will be set as missing. 
• 
Open-label Study Baseline for Group 1, 2 and 3 is defined as the average of open-label Day 
1 pre-dose assessment and the last measurement prior to open-label Day 1. If one of the 
two measurements is missing, then the other measurement will be assigned as the baseline 
value.  If both are missing, then the baseline will be set as missing. 
Baselines for QOL (EQ-5D, SF-36):  
1. Index Study Baseline for Group 1 is defined as the last non-missing assessment on Week 1 of 
treatment, volanesorsen or Placebo, in index studies. 
2. Open-label Study Baseline for Group 1, 2 and 3 is defined as the last non-missing assessment on 
Week 1 in this Open-label study.  
Baselines for patient reported abdominal pain:  
1. The average of maximum intensity:  
2. Index Study Baseline for Group 1 is defined as the average of maximum intensity during the 
screening period and Week 1 in index studies. 
3. Open-label Study Baseline for Group 1, 2 and 3 is defined as the average of maximum intensity 
within 4 weeks (including week 1) prior to Day 1 of treatment in this open-label study.  
4. The worst of maximum intensity: 
5. Index Study Baseline for Group 1 is defined as the worst of maximum intensity during the 
screening period and Week 1 in index studies. 
6. Open-label Study Baseline for Group 1, 2 and 3 is defined as the worst of maximum intensity 
within 4 weeks (including week 1) prior to Day 1 of treatment in this open-label study. 
Safety Baseline for Platelet count: is defined as the average of all available measurements, including 
central lab measurements and local lab measurements, prior to Day 1 of volanesorsen, i.e.  
1. 
For subjects in Group 1 and 2 who were treated with volanesorsen in the index 
study, it is all available measurements prior to Day 1 of treatment in index study  
2. 
For subjects in Group 3, it is all available measurements prior to Day 1 of treatment 
in this Open-label study  


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3. 
For subjects in Group 1 and 2 who were treated as placebo in the index study, it is 
all available measurements within 4 weeks prior to Day 1 of volanesorsen in this 
open-label study. 
Safety Baselines for 12-lead ECG: is defined as the average of the triplicate ECGs taken on screening 
visit of this Open-label study or the last visit in the parent study, if only one or two assessments are 
available, the single assessment or average of the two assessments will be used. 
4. 
For subjects in Group 1 and 2 who were treated as volanesorsen in the index study, 
it is the last visit prior to Day 1 of treatment in index study  
5. 
For subjects in Group 3 and subjects in Group 1 and 2 who were treated as placebo 
in the index study, it is the last visit prior to Day 1 of treatment in this Open-label 
study  
Safety Baselines for vital sign, clinical safety lab (except for the platelet) and MRI  
It is defined as last non-missing assessment prior to Study Day 1 pre-dose of volanesorsen in index 
studies or Open-label study.   
Safety Baselines for MRI: is defined as last non-missing assessment on or prior to Study Day 14 of 
volanesorsen in index studies or Open-label study.   
Baselines for analyses: 
• 
Efficacy analyses are based on the Index study Baseline and the Open-label study Baseline. 
Details of separate analyses based on each baseline will be specified in the section 3.3.  
• 
Safety analyses are based on Safety Baseline. Details of separate analyses based on each 
baseline will be specified in the section 3.5.  
3.2.4 
Patient Baseline data, Medical history and Disposition 
Summary tables in this section will be presented for the FAS by the group presented in Section 3.2.1.  
Baseline data (demographic, disease history and baseline disease characteristics) will be 
summarized. It will also be displayed in the patient data listings.  
• 
Demographic including age, gender, ethnicity, race, weight and BMI will be summarized 
using descriptive statistics by the group presented in Section 3.2.1. Age is calculated by 
using the informed consent date of the open-label study and birth date. Gender, ethnicity 
and race for Group 1 and 2 patients were collected in each index study.    
• 
Disease history includes duration of FCS diagnosis at screening, age at FCS diagnosis, 
lipemia retinalis, eruptive xanthomas history, pancreatitis history, glybera treatment 
history, confirmation for known loss-of-function mutations in Type 1-causing genes, 
documentation of post heparin plasma LPL activity <=20% of normal based on medical 
history, confirmation for type 1 phenotype based on genetic sequencing results, post 
heparin plasma LPL activity <=20% of normal based on lab results, , and history of type II 
diabetes. 


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• 
Baseline disease characteristics includes: body weight, height at Day 1 of the Open-label 
study, Body Mass Index (BMI) , fasting lipids results including TG, LDL-C, HDL-C, Total 
Cholesterol, non-HDL-C, VLDL-C, apoA-1, apoB and apoC-III. 
Medical history collected in the open-label study will be coded by Medical Dictionary for Regulatory 
Activities (MedDRATM) dictionary version 19.1 and will be summarized by system organ class and 
preferred term for the Safety Set. Medical history will also be provided in the patient data listings.  
Patient disposition of the open-label study will be summarized for all enrolled patients. The number 
of patients enrolled, dosed, completed treatment, along with reasons for discontinuing treatment 
and withdrawing from the study, completed post-treatment follow-up, along with reasons for early 
terminating post-treatment follow-up, will be presented. Patient disposition through CS6 and CS7 
will also be summarized. 
Treatment discontinuation by month will be presented through index studies and open-label study 
to present number of patients discontinued in each study month and corresponding discontinuation 
reason, and remaining number of patients in the study. 
Summary of discontinuation rate per patient year of exposure in the index studies and open-label 
study overall will be generated. 
Kaplan Meier Plot of Treatment Continuation will be provided for below comparisons:  
• 
CS6 volanesorsen arm vs CS7 treatment naive group in patients with history of pancreatitis 
• 
CS6 volanesorsen arm vs CS7 treatment naive group in patients with history of pancreatitis 
through Month 12 
• 
CS6 volanesorsen arm vs CS7 treatment naive group in safety set through Month 12 
Listing of patient disposition will also be provided.   
 
3.3 
Efficacy Analysis 
Efficacy endpoints include: percent change and change in fasting lipid measurements, frequency and 
severity of patient reported abdominal pain, change from baseline in QOL, adjudicated acute 
pancreatitis events rate and frequency of other symptoms. 
Efficacy analyses will be conducted in the FAS by the group presented in Section 3.2.1.  
For fasting lipid measurements and QOL (EQ-5D, SF-36), both the Index Study Baseline and the 
Open-label Study Baseline will be used. In the summary tables using the Open-label Study Baseline, 
visits are mapped to analysis visits as shown in Section 3.2.1 for fasting lipid measurements and QOL 
(EQ-5D, SF-36) in the open-label study. In the summary tables using the Index Study Baseline, visits 
include the index study baseline visit, and the open-label study mapped post baseline visits.  
Efficacy analyses for the fasting TG will be performed on FAS. 
By patient listings will have all efficacy endpoints results collected in the open-label study.  


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Summary table and by patient listing will be generated by visit window, dose level, fasting TG and 
corresponding change from baseline value, nadir platelet, any pre-treatment adjudicated 
pancreatitis events, and abdominal pain event (average of intensity and yearly rate of frequency of 
moderate or severe events). Below visit windows will be utilized:  
Visit Window 
Dose Level 
TG 
Platelet Nadir 
Abdominal Pain 
0-3 months 
week 1-13 
month 3 
day 1-91 
week 2-14 
3-6 months 
week 14-26 
month 6 
day 92-182 
week 15-27 
6-9 months 
week 27-39 
week 38 
day 183-273 
week 28-40 
9-12 months 
week 40-52 
month 12 
day 274-364 
week 41-53 
12-15 months 
week 53-65 
week 64 
day 365-455 
week 54-66 
15-18 months 
week 66-78 
week 76 
day 456-546 
week 67-79 
18-21 months 
week 79-91 
week 90 
day 547-637 
week 80-92 
21-24 months 
week 92-104 
week 104 
day 638-728 
week 93-105 
24-27 months 
week 105-117 
week 117 
day 729-819 
week 106-118 
3.3.2 
Percent change and absolute change from baseline in fasting TG  
The Month 3 analysis time point is at the end of Month 3 where the value is defined as the average 
of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments.  If one visit is missing, then the 
other visit will be used as the 3-month endpoint.  If both visits are missing, then the 3-month 
endpoint will be set as missing. 
The Month 6 analysis time point is at the end of Month 6 where the value is defined as the average 
of Week 25 (Day 169) and Week 26 (Day 176) fasting assessments.  If one visit is missing, then the 
other visit will be used as the 6-month endpoint.  If both visits are missing, then the 6-month 
endpoint will be set as missing. 
The Month 12 analysis time point is at the end of Month 12 where the value defined as the average 
of Week 50 (Day 344) and Week 52 (Day 358) fasting assessments.  If one visit is missing, then the 
other visit will be used as the 12-month endpoint.  If both visits are missing, then the 12-month 
endpoint will be set as missing. 
Percent change and absolute change from the Open-label Study Baseline at Month 3, Month 6, and 
Month 12 in this open label study, and percent change and absolute change from the Index Study 
Baseline in fasting TG at index study Month 3, Month 6, and Month 12, and the open label study 
Month 3, Month 6, and Month 12 will be summarized.  For patients enrolled to extended treatment 
period, percent change and absolute change from the Open-label Study Baseline and percent 
change and absolute change from the Index Study Baseline in fasting TG at Week 64, 76, 90, and 
104 will also be summarized.  
These analyses will be repeated using on-treatment period data, which is defined as the last dose 
date of study medication + 28 days.  
A descriptive summary of TG over time will be conducted overall and by age group (<65 years vs. 
>=65 years). A descriptive summary of TG over time during on-treatment period will also be 
conducted overall. 


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3.3.3 
Treatment response rates  
Treatment response rate, where  patients with fasting plasma TG < 750 mg/dL or achieving fasting 
TG ≥ 40% reduction from baseline at Month 3, Month 6, and Month 12 will be summarized overall 
and by age group (<65 years vs. >=65 years).  Four response rates are defined as following: 
- 
Response rate 1 is defined as the proportion of patients with fasting plasma TG < 750 mg/dL 
at Month 3, Month 6, or Month 12 in the subset of patients with the Open-label Study 
Baseline fasting plasma TG ≥ 750 mg/dL.   
- 
Response rate 2 is defined as the proportion of patients with fasting plasma TG < 750 mg/dL 
at Month 3, Month 6, or Month 12 in the subset of patients with the Index Study Baseline 
fasting plasma TG ≥ 750 mg/dL.   
- 
Response rate 3 is defined as the proportion of patients who achieve fasting TG ≥ 40% 
reduction from the Open-label Study Baseline at Month 3, Month 6, or Month 12 for all 
patients with both baseline and post baseline results.   
- 
Response rate 4 is defined as the proportion of patients who achieve fasting TG ≥ 40% 
reduction from the Index Study Baseline at Month 3, Month 6, or Month 12 for all patients 
with both baseline and post baseline results.   
Response analysis will also be conducted using a range of fasting plasma TG thresholds for 
determination of responder status. 
- 
Response rate 1 and 2 will also be conducted by using other response thresholds (e.g., 500, 
880, 1000 mg/dL).   
- 
Response rate 3 and 4 will also be conducted by using other response thresholds (e.g., ≥ 
20%, 30%, 50%, 60%, 70% reduction).   
Patients with both baseline and post baseline results will be included in the summary and counted in 
the denominators. Missing baseline or post baseline results will be excluded from the summary. 
3.3.4 
Incremental effects of volanesorsen on lipid measures  
The incremental effects of volanesorsen on fasting TG and other fasting lipid measurements will be 
explored and the association between percent changes in fasting lipid measurements and total 
amount of drug received will be examined. Scatter plots of percent change from baseline in fasting 
lipid measurements including TG, non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C,  LDL-C, total cholesterol, 
and total apoC-III versus total amount of volanesorsen received and corresponding Pearson’s 
correlation coefficient will be presented. For patients treated with volanesorsen in index studies, the 
Index Study Baseline will be used, and for patients treated with placebo in index studies and Group 
3 patients, the Open-label Study Baseline will be used. The total amount of doses will be the total 
number of injections (volanesorsen) received from both index studies and open-label study 
regardless if full dosing is administered or not. 
All patients will be presented in the same graph no matter if the patient is from the index studies or 
the open-label study. 


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3.3.5 
Frequency and severity of patient reported abdominal pain 
The maximum intensity of abdominal pain related to disease will be collected on the FCS symptom 
questionnaire and reported by patients weekly on Bracket electronic patient reported outcomes 
(ePRO). The average maximum intensity of patient reported abdominal pain score during the on-
treatment period will be summarized. The patients’ reported results will be mapped to each visit 
week based on the visit window specified in section 3.2.1. If patients have multiple results within a 
visit window, the worst score will be used for summary and analysis. The results at Week 1 will not 
be included in the on-treatment period, since the results are reported retrospectively to collect the 
symptoms of patients during the past week. The missing data will be imputed by using Next 
Observation Carried Back (NOCB) if there is a subsequent score available.  Otherwise, the missing 
data after the last available score of each patient will not be imputed. 
Two (2) types of summary tables will be provided in the subset of FAS patients who reported any 
abdominal pain (pain score > 0) during the screening period and Week 1. Baselines are defined in 
the section 3.2.3. 
1. Change from both Index Study Baseline and Open-label Study Baseline in the average of 
maximum intensity of patient reported abdominal pain will be summarized.   
2. Change from both Index Study Baseline and Open-label Study Baseline in the worst weekly 
patient reported maximum intensity abdominal pain score during the treatment period will 
be summarized.     
3. The same method described above will be used to impute the missing data in exploratory 
analyses. 
The abdominal pain score in each week will be categorized to no pain (pain score: 0), mild (pain 
score: 1–3), moderate (pain score: 4–6), or severe (pain score: 7–10). A summary by the category 
will also be provided for safety set overall, and for CS6 subjects who roll-over to CS7. Other 
information of the abdominal pain questionnaires will be listed in a patient data listing. 
Summary table and figure for abdominal pain intensity change for patients with pain at baseline in 
CS6 subjects who roll-over to CS7 will be generated.   
3.3.6 
Percent change and change from baseline in other fasting lipid measurements 
Percent change and absolute change from the Open-label Study Baseline at Month 3, Month 6, and 
Month 12 in this open label study, and percent change and absolute change from the Index Study 
Baseline in other fasting lipid measurements including total cholesterol, non-HDL-C, apoB, HDL-C, 
apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C at index study Month 3, Month 6, and Month, and 
the open label study Month 3, Month 6, and Month 12 will be summarized.  For patients enrolled to 
extended treatment period, percent change and absolute change from the Open-label Study 
Baseline and percent change and absolute change from the Index Study Baseline in fasting TG at 
Week 64, 76, 90, and 104 will also be summarized. A descriptive summary of these measurements 
over time will also be conducted overall and by age group (<65 years vs. >=65 years). 


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3.3.7 
Percent change and change from baseline in fasting total apoC-III 
Percent change and absolute change from the Open-label Study Baseline at Month 3, Month 6, and 
Month 12 in this open label study and percent change and absolute change from the Index Study 
Baseline in fasting total apoC-III at index study Month 3, Month 6, and Month, and the open label 
study Month 3, Month 6, and Month 12 will be summarized.  For patients enrolled to extended 
treatment period, percent change and absolute change from the Open-label Study Baseline and 
percent change and absolute change from the Index Study Baseline in fasting TG at Week 64, 76, 
90, and 104 will also be summarized. A descriptive summary of fasting total apoC-III over time will 
also be conducted. 
3.3.8 
Change from baseline in Quality of Life (QOL) questionnaires (EQ-5D, SF-36) 
QOL Questionnaires (EQ-5D and SF-36) will be completed by patients at Baseline, Week 13, Week 26 
and Week 52 and Week 65.  
A shift table for EQ-5D QOL Questionnaire will be provided with the shift from the Index Study 
Baseline level and from the Open-label Study Baseline level for each dimension (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) to post-baseline visit level.  In the shift 
table, slight and moderate will be combined as one level, and severe and unable will be combined as 
one level.  The health status visual acuity score (VAS), as well as the scores for all dimensions, will be 
summarized for baseline, post-baseline visit, and the change from baseline at post-baseline visit will 
be summarized also. 
The results of the mean weighted scores for all sections from the SF-36 QOL Questionnaire (vitality, 
physical functioning, bodily pain, general health perceptions, physical role functioning, emotional 
role functioning, social role functioning, and mental health) will be summarized for baseline, post-
baseline visit, and the change from baseline at post-baseline visit will be summarized also. Both the 
Index Study Baseline and the Open-label Study Baseline will be used. 
Note: Group 2 patients have no QOL assessment in the index study (ISIS 304801-CS16). 
3.3.9 
Adjudicated acute pancreatitis events Rate  
Yearly rate of adjudicated acute pancreatitis events and patient reported moderate or severe 
abdominal pain (pain score:  4-10) for FAS during the on-treatment period of the Open-label study, 
calculated as 365.25 x the number of events during the on-treatment period / on-treatment 
duration, will be summarized with descriptive statistics. At each mapped visit window of abdominal 
pain, at most one moderate or severe event will be counted to calculate the yearly rate. Adjudicated 
acute pancreatitis event rate prior to first dose of Study Drug (including events based on medical 
chart review) vs. treatment emergent events will be summarized. 
Yearly rate of adjudicated acute pancreatitis events and patient reported moderate or severe 
abdominal pain (pain score:  4-10) for patients who administered volanesorsen in Index studies will 
be calculated and summarized, including events occurred during either index study or open-label 
study.  


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On-study and on-treatment pancreatitis incidence rate per patient year of exposure will be 
summarized.  
3.3.10 Frequency of other symptoms: eruptive xanthoma, lipemia retinalis 
Percentage of patients who experienced eruptive xanthoma during the treatment period of the 
Open-label study will be summarized. Counts and percentages of the worst severity of eruptive 
xanthoma will be provided.  Yearly rate during the treatment period of the Open-label study, 
calculated as 365.25 x the number of events during the treatment period / treatment duration, will 
be summarized with descriptive statistics. 
Yearly rate of eruptive xanthoma for patients who administered volanesorsen in the Index study CS6 
will be calculated and summarized, including events occurred during either index study or open-
label study.  
Counts and percentages of lipemia retinalis will be summarized by visits. 
3.4 
Pharmacokinetic and Immunogenicity Analysis 
PK concentration and Immunogenicity (IM) results obtained in the open-label study will be 
summarized along with those from the index study. Patient data listings will also be provided. 
3.4.1 
Pharmacokinetic Analysis 
PK analyses will be conducted in PK population. 
3.4.1.1 All patients 
During the treatment period, blood samples for the determination of plasma volanesorsen 
concentrations will be collected prior to dosing, and at various times throughout the dosing and 
post-treatment follow-up period as noted in the tables below. 
PK Sampling Schedule (All Patients except PK Subgroup) 
Week 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65* 
Study Day 
D1 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
* Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 
PK Sampling Schedule (Extended Treatment Period) 
Week 
Wk 76 
Wk 104 
Wk 117 
Study Day 
D526 
D722 
D813 
Visit Window 
2 
2 
7 


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+/- Days 
Time Point 
Pre-dose 
Pre-dose 
Anytime 
For all patients, plasma concentrations of volanesorsen, along with the scheduled (nominal) and 
actual sampling times (i.e., time from SC dosing) will be listed (when applicable) for Group 1 and 
Group 2 patients by their prior treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and newly 
enrolled patients as a separate group (Group 3), dose, patient ID, patient immunogenicity (IM) 
status, and IM onset (if applicable) as defined in Section 3.4.2, and day. Plasma concentrations 
below the lower limit of quantification (LLOQ) will be presented as “0.00”.  In addition, percent 
differences between scheduled and actual sampling times will also be listed. 
For all patients, trough (pre-dose) and post-treatment volanesorsen plasma concentrations will be 
summarized by the group presented in Section 3.2.1, study day, with and without stratification by 
IM status, using descriptive statistics (n, mean, SD, SEM, %CV, geometric mean, geometric %CV, 
median, minimum, and maximum). For the purpose of calculating typical descriptive statistics for 
plasma concentrations, all below the lower limit of quantification (BLQ) values will be set to zero. 
Mean plasma concentrations that are BLQ will be presented as BLQ, and the SD and %CV will be 
reported as “NA” (not applicable). At the discretion of the pharmacokineticist and/or biostatistician, 
samples may be excluded from descriptive statistics if there are large deviations between scheduled 
and actual sampling times, or large deviations between actual dose and nominal dose. 
Mean (±SD) plasma volanesorsen concentration-time plots with and without stratification by 
immunogenicity status will be generated. 
3.4.1.2 PK subgroup 
A subgroup of patients will participate in an extended PK collection.  The detailed PK sampling 
schedules are outlined below. Patients continuing to receive volanesorsen beyond Week 52 will 
follow the PK sampling schedule in the extended treatment period: 
PK Sampling Schedule (PK Subgroup only*) 
Week 
Wk 
1 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
13 
Wk 
26 
Wk 
38 
Wk 
52 
Wk 
65** 
Study Day 
D1 
D2 
D22 
D50 
D85 
D176 
D260 
D358 
D449 
Visit Window 
+/- Days 
0 
0 
2 
2 
2 
2 
3 
2 
7 
Time Point 
Pre-dose, 
1, 2, 3, 4, 
6, 8, and 
12 hrs 
post-dose 
24 hrs 
post-dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
* 
Patients at selected sites will be asked to participate in the extended 24-hour PK profile beginning on 
Study Day 1.  Participation is optional 
** Week 65 PK collection will be omitted for patients continuing to receive volanesorsen beyond Week 52 


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For patients in the PK subgroup only, non-compartmental PK analysis of volanesorsen will be carried 
out on each individual patient data set using data collected in the open-label study from the 
intensive PK subgroup, following a single dose (i.e., single-dose PK) or multiple doses (i.e., steady-
state PK), depending on their earlier treatment in the index studies (Group 1 and Group 2 Patient).  
On Week 1 Day 1 of the open-label study, patients who received placebo in the index study (and all 
patients in Group3) will receive the first treatment of volanesorsen (single-dose PK), while patients 
who received volanesorsen in the index studies had been on volanesorsen treatment for 12 months 
(ISIS 304801-CS6) or 6 months (ISIS 304801-CS16), thus the PK data collected from these patients 
reflect steady-state PK.  The maximum observed drug concentration (Cmax) and the time taken to 
reach Cmax (Tmax) will be obtained directly from the concentration-time data.  Area under the plasma 
concentration-time curve from time zero to 24 hours (AUC0-24h) will be calculated using the linear 
trapezoidal rule.  Apparent systemic (plasma) clearance after SC administration (CL0-24h /F) will be 
calculated from CL0-24h /F = Actual Dose/AUC0-24h.  Mean residence time (MRT) from time zero to 24 
hours after the SC administration will be calculated from the equation, MRT0-24h = AUMC0-24h /AUC0-
24h, where AUMC0-24h is the area under the moment plasma concentration-time curve from time zero 
to 24 hours after the SC administration.  Other PK parameters, as appropriate, may be determined 
or calculated at the discretion of the PK scientist. 
Plasma PK parameters will be summarized using descriptive statistics for 2 groups (Treatment naive 
group and CS6-Volanesorsen and CS16-Volanesorsen Combined), with and without stratification by 
IM status.   
Population PK, PK/PD, and covariate analysis may be performed if deemed appropriate, and results 
will be reported separately. This SAP do not include relevant analysis plan. 
3.4.2 
Immunogenicity (IM) Analysis 
Immunogenicity (IM) analyses will be conducted in Safety Set. 
Samples collected for IM assessment at selected time points will be analyzed for anti-volanesorsen 
antibodies (i.e., anti-drug antibodies; ADA).  Samples will be designated ‘IM positive’ based on both 
positive screening and confirmation assay results (i.e., confirmed positive result), and otherwise be 
deemed ‘IM negative’.  Study subjects will be given ‘positive’ subject IM status if they have at least 
one confirmed positive sample at any time during the treatment or post-treatment evaluation 
periods.  Study subjects will be given ‘negative’ subject IM status if all evaluated IM sample results 
during the treatment and post-treatment evaluation periods are negative and they have at least one 
evaluable IM result post dose.  Otherwise, study subjects will be given ‘unknown’ subject IM status. 
Sample IM status (screen positive/negative, confirmed positive/negative or not evaluable, and when 
applicable, titer of anti-volanesorsen antibodies) before, during, and after treatment with Study 
Drug (volanesorsen or placebo) will be listed for Group 1 and Group 2 patients by their prior 
treatment in Study ISIS 304801-CS6 and ISIS 304801-CS16 and newly enrolled patients as a separate 
group (Group 3) by study day.  Subject IM status (positive/negative or unknown) for all evaluable 
patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast) and max and/or end of 
treatment titer will be listed by treatment and dose. 


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Additionally, the sample and patient IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated patients with antibody negative, positive, 
and unknown status by the group presented in Section 3.2.1.  Furthermore, onset, and peak titer of 
the ADA response, if applicable, will be summarized as median, interquartile range (25th percentile, 
75th percentile), and range (minimum, maximum). 
Potential relationships between immunogenicity results (e.g., IM status) and selected efficacy (e.g., 
% change in fasting TG from baseline at 3-, 6-, and 12-month endpoints), safety, and 
pharmacokinetic measures will be evaluated in an exploratory manner.   
3.5 
Safety Analyses 
Safety endpoints including treatment exposure, AEs, clinical safety lab, vital signs, physical 
examination, 12-lead ECG, Echocardiogram, prior and concomitant medication use, and MRIs will be 
summarized in Safety Set.  
On-Study period (from Day 1 of Volanesorsen to end of the study) in the open-label study will be 
classified to 3 periods: 
• 
On-treatment period: from the first dose of Volanesorsen to the last dose of Volanesorsen + 
28 days 
• 
After-treatment period: from the last dose of Study Drug + 29 days to the last dose of study 
medication + 90 days 
• 
Post-follow up period:  after the last dose of Study Drug + 90 days 
For vital sign, clinical safety lab, or 12-lead ECG, 
• 
Visits of summary tables include baseline and labeled post baseline visits in the open-label 
study. 
• 
Safety Baseline is defined in the section 3.2.3 of this SAP.  
For AEs, prior and concomitant medication use, each summary table will present the open-label 
study data.  
For treatment exposure, details are discussed in the section 3.5.5 of this SAP. 
By patient data listings will display data collected in the open-label study.  
In this section, Day 1 of Volanesorsen is defined as the first day volanesorsen is administered to the 
patient. For patients on active treatment in the index study, Day 1 of Volanesorsen will be the first 
day volanesorsen is administered in the index study.  For patients on placebo in the index study, Day 
1 of Volanesorsen will be the first day volanesorsen is administered in this open-label study. 
Patient profile figures will be generated for selected patients to provide graphical profile of endpoint 
of interest.  


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3.5.1 
Imputation of Missing/Partial Dates 
3.5.1.1 Adverse Events 
For AEs, the following imputation rules will be applied to impute start dates under conservative 
principles: 
• 
If year, month and day are all missing then assign Day 1 of Volanesorsen. 
• 
If month and day are missing and year is 
o The same as the year of Day 1 of Volanesorsen then assign the month-day of first 
Study Drug. 
o Earlier than the year of Day 1 of Volanesorsen then assign December 31. 
o After the year of Day 1 of Volanesorsen then assign January 1. 
If only day is missing and month-year is 
o The same as the month-year of Day 1 of Volanesorsen then assign the day of first 
Study Drug. 
o Earlier than the month-year of Day 1 of Volanesorsen then assign the last day of the 
month. 
o After the month-year of Day 1 of Volanesorsen then assign the first day of the 
month. 
Imputation will be performed only for the end date only if the day or month is missing (i.e. year is 
present) for a resolved AE as follows: 
• 
If month and day are missing and year is 
o The same as the year of the last dose of Study Drug then assign the month-day of 
the last dose of Study Drug.  
o Otherwise, assign December 31. 
• 
If only day is missing then assign the last day of the month. 
If the imputed start date is later than the imputed end date then set the imputed start date to the 
imputed end date. 
3.5.1.2 Prior/Concomitant Medications 
For prior/concomitant medications, the following imputation rules will be applied to impute start 
dates under conservative principles: 
• 
If year, month and day are all missing then assign the date of Day 1 of Volanesorsen. 
• 
If month and day are missing and year is 
o Earlier than the year of Day 1 of Volanesorsen then assign December 31. 


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o Otherwise, assign January 1. 
• 
If only day is missing and month-year is 
o Earlier than the month-year of Day 1 of Volanesorsen then assign the first day of 
the month. 
o Otherwise, assign the last day of the month. 
Imputation will be performed only for the end date only if the day or month is missing (i.e. year is 
present) for a stopped prior/concomitant medication as follows: 
• 
If month and day are missing then assign December 31. 
• 
If only day is missing then assign the last day of the month. 
If the imputed start date is later than the imputed end date then set the imputed start date to the 
imputed end date. 
3.5.2 
Adverse Events 
3.5.2.1 General Analysis of AEs 
All adverse events will be coded by the MedDRA coding system.  Missing or partial dates will be 
imputed as outlined in section 3.5.1.1. A treatment emergent adverse event (TEAE) is defined as any 
event starting or getting worse on or after Day 1 of Volanesorsen 
In the situation where change in severity (but no change in seriousness) occurs for an adverse event, 
study sites are instructed to enter an end date and start a new record for the adverse event. In the 
new record, the changed severity is to be recorded and the start date will be set to be the end date 
of the previous record. Data linking those records are collected in the data set “Formlinks”.  
TEAE will be identified as follows based on the (imputed) AE start dates: 
Case 1: If there is no “Formlink” link, and the AE (start date/time) occurs on or after the patient’s 
first dosing date/time on Day 1 of Volanesorsen, then the AE is treatment-emergent. Otherwise, if 
the AE (start date/time) occurs prior to the patient’s first dosing date/time on Day 1 of 
Volanesorsen, then the AE is not treatment-emergent.  
Case 2: If there is a “Formlink” link between two AE records, then the two AE records will be 
chronologically ordered by AE start date/time and will be referred to as the “first” and the “second” 
AE respectively. AE severity (mild/moderate/severe) will then be compared pairwise.   
Case 2a:  The first AE record in the pair occurs before first dosing on Day 1 of Volanesorsen, and the 
second record occurs on/after dosing.   
If the AE severity on the second record is worse than the severity on the first record or the second 
record is changed to serious, then only count the second AE as treatment-emergent.  But, if the 
severity doesn’t worsen (i.e. the second record severity is the same or less severe than the first 


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record severity) and the serious result is not changed from non-serious to serious, then neither 
record is counted as treatment-emergent. 
Case 2b:  Both AE records in the pair occur on/after first dosing on Day 1 of Volanesorsen.   
If the AE severity on the second record is worse than the severity on the first record or the second 
record is changed to serious, then count both records as treatment-emergent.  But, if the severity 
doesn’t worsen and the serious result is not changed from non-serious to serious, then only count 
the first record as treatment-emergent. 
Case 2c: Both AE records in the pair occur before first dosing on Day 1 of Volanesorsen. 
Neither AE is counted as treatment-emergent. 
When counting the total number of treatment-emergent events, events linked together through 
change in severity will still be counted as separate events. 
TEAE will be classified into three periods: on-treatment, after-treatment, and post-follow up periods 
and are defined as follows based on (imputed) start date of the event. 
The frequency of patients with any incidence of AEs and the number of events will be summarized 
by MedDRA preferred term and system organ class for: 
1. Any TEAE, any on-treatment TEAE, any after-treatment TEAE. 
2. TEAEs related to Study Drug. Related is defined as “Related”, “Possible”, or missing 
relationship to Study Drug. 
3. Any treatment emergent adverse event by severity. At each level of patient summarization, 
a patient with multiple events is counted only once according to the worst reported 
severity. Adverse events with missing severity will be categorized as “Missing” for this 
summary. 
4. TEAEs potentially related to Study Drug by severity.  
5. Post-follow up adverse events 
6. Serious TEAEs. 
7. Serious on-treatment TEAE. 
8. Serious TEAEs potentially related to Study Drug. 
9. AEs leading to permanent treatment discontinuation, and 
10. TEAEs leading to death. 
Adverse event summaries will be presented alphabetically and by descending frequency of the 
percentage of patients in the overall column. An overview of AEs will be provided for all TEAEs, on-
treatment TEAEs, and after-treatment AEs.  Treatment-emergent AEs, treatment emergent SAEs, 
AEs that lead to treatment discontinuation, and TEAEs leading to death will be listed.  Note that 


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imputed dates will be used for defining TEAEs and classification of TEAEs into on-treatment, after-
treatment, and post-follow up periods. Originally reported dates will be used for listings.  
On-study AEs will be also summarized by treatment and age for FCS patients and all patients in 
safety set. 
Treatment emergent renal adverse events will be summarized.  
In addition, an overview of adjudicated AEs will be provided for pancreatitis and MACE separately. 
Adjudicated events will also be listed. 
3.5.2.2 Adverse Events of Special Interest  
The following events are considered to be clinically-relevant and will be summarized: 
• 
 Platelet count reduction to< 50,000/mm3 associated with major bleeding or 
clinically-relevant non-major bleeding 
• 
Platelet count reduction to < 25,000/mm3, irrespective of bleeding status  
3.5.2.3 Other Events of Interest 
Local Cutaneous Reactions at the Injection Site (LCRIS) 
Local cutaneous reactions at injection site (LCRIS) will also be summarized by the group presented in 
Section 3.2.1 including overall using the MedDRA coding system, by system organ class and 
preferred term. Number and percent of patients reporting at least one LCRIS will be summarized 
also. 
The following MedDRA preferred terms are determined by the Sponsor’s Pharmacovigilance 
personnel to represent the local cutaneous reaction at the injection site: 
• 
Injection site erythema  
• 
Injection site swelling  
• 
Injection site pruritus  
• 
Injection site pain  
• 
Injection site tenderness 
Only events that start on the day of injection and persist for at least 2 days, i.e. event onset date on 
the day of injection and resolution date not on the day of injection or the day after the injection, will 
be included.  Events with onset date on the day of injection and missing resolution date will also be 
included. 
Percentage of injections leading to local cutaneous reactions at injection site will be summarized by 
the group presented in Section 3.2.1 including overall using descriptive statistics. 
Percentage of injections leading to local cutaneous reactions at the injection site will be calculated 
as follows for each patient: (A/B)*100, where A=number of injections leading to local cutaneous 
reactions at the injection site, and B=total number of injections.  


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Revised LCRIS is defined as any AE with MedDRA preferred term or verbatim that contains 
“INJECTION SITE”. Revised LCRIS that start on the day of injection and persist for at least 2 days, and 
revised LCRIS that start any time and persist for at least 2 days, will be included.  
Number of total volanesorsen injections in index study and/or open-label study before the first 
treatment emergent revised LCRIS will be summarized. 
Duration to resolution in days will be calculated as the summation of (AE end date – AE start date) + 
1 for all treatment emergent LCRIS related to one injection. For LCRIS events with overlapped 
duration related to one injection, the earliest start date and latest end date will be used in the 
calculation; for unresolved LCRIS events with missing end date, the last date on study will be used in 
the calculation. 
Discoloration  
Discoloration is defined as any AE with “Injection Site Discolouration” as MedDRA preferred term. 
Counts and percentages of patients with any discoloration TEAE and unresolved discoloration TEAE 
will be summarized. 
Flu-Like Reactions 
Flu-like reactions (FLRs) will also be summarized by the group presented in Section 3.2.1 including 
overall using the MedDRA coding system, by system organ class and preferred term and by 
preferred term only. Number and percent of patients reporting at least one FLR will be summarized 
also. 
FLRs are defined as either (A) flu-like illness or (B) Pyrexia or feeling hot or body temperature 
increased, plus at least two of the following: Chills, Myalgia, and Arthralgia, starting on day of 
injection or the next day.  
Percentage of injections leading to FLRs will be summarized by the group presented in Section 3.2.1 
including overall using descriptive statistics. 
Percentage of the injections leading to FLRs will be calculated as follows for each patient: (A/B)*100, 
where A=number of injections leading to FLRs, and B=total number of injections. 
Revised FLRs are defined as flu-like illness, chills, myalgia, arthralgia, pyrexia, feeling hot, body 
temperature increased that starts on the day of volanesorsen injection or the next day. 
Bleeding Adverse Events  
Treatment Emergent bleeding adverse events also will be summarized using MedDRA preferred 
term and system organ class. The bleeding TEAE will be defined based on the Haemorrhages (SMQ) 
Export from MedDRA. 
The frequency of patients with any incidence of AEs and the number of events will be summarized 
by MedDRA preferred term (and severity) sorted by frequency for: 


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1. Any treatment emergent bleeding AEs for the safety set, for the subset of patients on 
concomitant anti-coagulant or anti-platelet medication, and for the subset of patients not 
on concomitant anti-coagulant or anti-platelet medication. 
2. Treatment emergent bleeding AEs under contemporaneous use of concomitant anti-coagulant 
or anti-platelet medication for the subset of patients on concomitant anti-coagulant or anti-
platelet medication. 
Treatment emergent bleeding adverse events will be listed. In addition, treatment emergent 
bleeding adverse events will be listed by platelet count categories before and after bleeding, and 
anti-platelet or anti-coagulant medication. 
Platelet Count Decreased/Thrombocytopenia Events 
Platelet count decreased or thrombocytopenia events will be listed by preferred terms, severity, 
platelet count category, platelet count before (or on)/after AE, and CTCAE grade of platelet count 
before (or on)/after AE.  
 
List of nadir post-baseline platelet count will be generated for patients who discontinued due to 
platelet count decreased or thrombocytopenia events.  
Any 2 Occurrences of Platelet Count < 140,000/mm3 or Any Single Occurrence of Platelet Count 
<100,000/mm3  
The analysis is defined in section 3.5.4.2. 
ALT > 3 ULN 
The analysis is defined in section 3.5.4.2. 
3.5.3 
Vital Signs Measurements 
Vital signs will include weight, BMI, body temperature, heart rate, respiratory rate, and systolic and 
diastolic blood pressure.  Summary tables will be created to present the descriptive statistics (n, 
mean, standard error, standard deviation, median, 25th percentile, 75th percentile, minimum, and 
maximum) for vital sign values as well as the change from baseline at each study visit. 
3.5.4 
Laboratory Measurements 
3.5.4.1  General analysis of safety laboratory data 
The following is the list of lab analytes that will be collected throughout the study: 
• 
Chemistry: Sodium, Potassium, Chloride, Bicarbonate, Total protein, Albumin, Calcium, 
Magnesium, Phosphorus, Glucose, Blood Urea Nitrogen (BUN), Creatinine, Uric Acid, Total 
bilirubin, Direct (conjugated) bilirubin, Indirect (unconjugated) bilirubin, Alanine 
aminotransferase (ALT), Aspartate aminotransferase (AST), and Alkaline  phosphatase.  
• 
Hematology: Red blood cells, Hemoglobin, Hematocrit, MCV, MCH, MCHC, Platelets, White 
blood cells (WBCs), and WBC differential in both percentage and absolute count 
(Neutrophils, Eosinophils, Basophils, Lymphocytes, and Monocytes) 


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• 
Coagulation: aPTT, PT, international normalized ratio (INR) 
• 
Other assessments: hs-CRP, C5a, Bb, Sedimentation rate, De-lipidated free glycerol, 
Glycated Hemoglobin (HbA1c), FPG 
• 
Urinalysis: Color, Appearance, Specific gravity, pH, Protein, Blood, Ketones, Urobilinogen, 
Glucose, Bilirubin, Leukocytes esterase, Nitrate, and Microscopic examination. For expanded 
urinalysis at certain visits, additional measurements will be performed including: Total 
Protein (quantitative), Microalbumin, and β2-microglobulin.  The expanded urinalysis data 
will be only displayed in patient data listings. 
Missing WBC differential absolute counts and percentages will be derived:  
If WBC differential absolute counts are missing, and percentages are available, then 
absolute counts will be calculated by multiplying the percentage by total WBC count.  
Conversely, if absolute count is available, and percentage is missing, then percentage will be 
calculated by dividing absolute count by the total WBC count.  If neutrophils counts and 
percentages are missing, and segmented neutrophil and band neutrophil results are 
available, then neutrophils will be calculated by adding segmented neutrophils and band 
neutrophils. 
The MDRD equation will be used to calculate Glomerular Filtration Rate (GFR) base on central lab 
serum creatinine (µmol/l) as: 
GFR (mL/min/1.73m2) = 32788 × Serum Creatinine (µmol/l) ^ (-1.154) × Age ^ (-0.203) × (1.210 if 
Black or African American) × (0.742 if female). 
All lab data will also be displayed in patient data listings based for all enrolled patients.  Chemistry, 
hematology, coagulation, other assessments and quantitative Urinalysis (result, change from safety 
baseline) will be summarized using descriptive statistics (n, mean, standard error, standard 
deviation, median, 25th percentile, 75th percentile, minimum, and maximum) by study visit. Counts 
and percentages of categorical lab results, e.g. Urine protein will be provided. 
3.5.4.2 Additional analyses of key safety laboratory data 
The following analyses of key safety laboratory data will be summarized for on-treatment period 
and on-study period respectively. 
The number and percent of patients falling in each of the following categories will be tabulated:  
• 
The higher of ALT > 3 x upper limit of normal (ULN) or ALT > 2 x Safety Baseline 
• 
ALT/AST > 3 x ULN 
• 
ALT/AST > 5 x ULN 
• 
ALT/AST > 8 x ULN 
• 
ALT/AST > 10 x ULN 
• 
ALT/AST > 20 x ULN 
• 
ALT > 3 x ULN - ≤ 5 x ULN 
• 
ALT > 5 x ULN - ≤ 10 x ULN 


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• 
ALT > 10 x ULN - ≤ 20 x ULN 
• 
Total bilirubin > 2 x ULN, and 
• 
ALP > 2 x ULN and (safety baseline ALP < 2 x ULN or safety baseline ALP missing) . 
The number and percent of patients falling in each of the following categories based on confirmed 
results after first dose will be tabulated (A confirmed value is based on a consecutive lab value 
within 7 days. If that value is in the same or worse category the initial value is confirmed. If the 
consecutive value is in a better category then the initial value is confirmed using the consecutive 
value category. If there is no retest within 7 days then the initial value is presumed confirmed. If 
there are multiple results on the same day, then the worst value will be utilized in the analysis):  
• 
The higher of ALT/AST > 3 x ULN or ALT/AST > 2 x Baseline, which is confirmed 
• 
ALT/AST > 3 x ULN, which is confirmed   
• 
ALT/AST > 5 x ULN, which is confirmed   
• 
ALT/AST > 10 x ULN, which is confirmed   
• 
ALT/AST > 20 x ULN, which is confirmed   
For patients having at least 3-fold or greater elevations above the ULN for ALT or AST, a listing of all 
of the ALT, AST, total bilirubin, INR, and alkaline phosphatase records will be provided. Other liver 
abnormalities including elevation of ALT (>3 x ULN) accompanied by elevated total bilirubin (> 2 x 
ULN), elevation of ALT (> 3 x ULN) accompanied by INR > 1.5 x ULN, elevation of ALT (> 3 x ULN) 
accompanied by elevated total bilirubin > 2 x ULN and ALP < 2 x ULN, and elevation of ALT/AST in 
temporal association with nausea, vomiting, anorexia, abdominal pain, or fatigue will be reviewed 
by the study team and summarized if needed. 
The following hematology and hepatic enzymes lab results will be categorized by value range based 
on Guidance for Industry – Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (September 2007), and the incidence of shift from 
safety baseline to worst post-baseline value taken after the first dose during on-treatment period 
will be summarized. If a patient is missing a safety baseline value but has a post-baseline value, then 
the baseline assessment will be labeled as “unknown”.  Likewise, if a patient has a baseline value but 
has no post-baseline values, then the worst value will be labeled as “unknown”. Number and 
proportion of patients with shift from safety baseline to worst post-baseline values based on the 
confirmed results by toxicity grade for ALT, AST, and platelets will also be tabulated. 
• 
Hemoglobin: shift from safety baseline to minimum post-baseline value 
• 
WBCs: shift from safety baseline to minimum post-baseline value  
• 
WBCs: shift from safety baseline to maximum post-baseline value  
• 
Platelets: shift from safety baseline to minimum post-baseline value  
• 
Creatinine: shift from safety baseline to maximum post-baseline value   
• 
BUN: shift from safety baseline to maximum post-baseline value 
• 
ALT: shift from safety baseline to maximum post-baseline value   
• 
AST: shift from safety baseline to maximum post-baseline value   
 
Hemoglobin change from baseline to minimum post-baseline value will be summarized by value 
category based on the toxicity grade as well.  


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Selected coagulation assessments shift from baseline to the worst post-baseline value will also be 
summarized by value category based on the toxicity grade.  
• 
Activated Partial Thromboplastin Time: shift from safety baseline to maximum post-baseline 
value 
• 
Prothrombin Time: shift from safety baseline to maximum post-baseline value 
• 
Prothrombin Intl. Normalized Ratio: shift from safety baseline to maximum post-baseline 
value 
• 
Fibrinogen: shift from safety baseline to minimum post-baseline value 
• 
Fibrinogen: shift from safety baseline to maximum post-baseline value 
 
LDL-C will be classified to ≥160 mg/dL (4.14 mmol/L) or <160 mg/dL (4.14 mmol/L), and the 
incidence rate of shift from safety baseline to maximum post-baseline category will be summarized.  
hsCRP will be classified to Normal or > Upper limit of normal (ULN), and the incidence rate of shift 
from safety baseline to maximum post-baseline category will be summarized. 
The incidence of patients with post-baseline platelet results falling in each of the following 
categories will be summarized for the safety set and the subset of patients with normal baseline 
(≥140,000/mm3), and these categories will be summarized based on confirmed values as well: 
• 
Any 2 occurrences of platelet count < 140,000/mm3 
• 
Any single occurrence of platelet count <100,000/mm3  
• 
Any 2 occurrences of platelet count < 140,000/mm3 or any single occurrence of platelet 
count <100,000/mm3  
• 
Worst post-baseline value falling in: 100,000/mm3 to < 140,000/mm3 , 75,000 to < 
100,000/mm3, 50,000 to < 75,000/mm3, 25,000 to < 50,000/mm3, 0 to < 25,000/mm3 
• 
Worst post-baseline platelet reduction from Baseline ≥ 30% and ≥ 50% 
The incidence of patients with post-baseline platelet results falling in each of the following 
categories will be summarized for the safety set and the subset of patients with normal baseline 
(≥140,000/mm3): 
• 
With >= 2 consecutive values of platelet count < 140,000/mm3 
• 
With platelet count <100,000/mm3 at final visit  
• 
With >= 2 consecutive values of platelet count < 140,000/mm3 or with platelet count 
<100,000/mm3 at final visit 
 
The number of patients with any single occurrence of platelet results at any time, and during post-
baseline period, falling in each of the following categories will be summarized for the safety set. 
These categories will be summarized based on nadir platelet values as well: 
• 
< 140,000/mm3 
• 
<100,000/mm3  
• 
100,000/mm3 to < 140,000/mm3  
• 
75,000 to < 100,000/mm3 


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• 
50,000 to < 75,000/mm3 
• 
25,000 to < 50,000/mm3 
• 
< 25,000/mm3 
 
The ratio of post-baseline central lab platelet test numbers to total number of injections in open-
label study will be summarized. The ratio of post-baseline central and local platelet tests numbers to 
total number of injections in open-label study will be also summarized. 
 
The time to recover from confirmed platelet values <100,000/mm3 during on-study period will be 
calculated and summarized by all patients, and patients who complete week 52 (or week 104) with 
or without any dose pause/dose adjustment.  
Summary figures will be generated for platelet counts over time (absolute values, absolute change 
from baseline, and percent change from baseline) in patients treated with placebo in ISIS 304801-
CS6 who then treated with Volanesorsen in ISIS 304801-CS7.  
A summary figure will be generated for platelet counts over time (mean and SEM of absolute values) 
for treatment naïve patients. The first event of platelet count < 50,000/mm3 will be annotated in the 
figure. This figure will also be generated by weight group (<70kg; >=70kg). 
A scatter plot will be generated for nadir platelet counts during on-treatment period vs. selected 
factors:  
Body Weight (kg) 
BMI 
The Total Number of Injections 
Baseline Spleen Volume (mL) 
Baseline Fasting Triglycerides (mmol/L) 
Baseline Fasting Apolipoprotein CIII (g/L) 
The incidence of patients with post-baseline lab results falling in each of the following categories will 
be summarized for the safety set: 
• 
Any serum creatinine >=0.3 mg/dL higher than baseline  
• 
Any serum creatinine >=50% higher than baseline 
• 
Final visit serum creatinine >=0.3 mg/dL higher than baseline  
• 
Final visit serum creatinine >=50% higher than baseline 
Summary of selected hematology assessment (white blood cell count, neutrophil, hemoglobin, and 
hematocrit) over time will be generated. Summary of selected urinalysis assessment (urinary 
protein, and urinary albumin), and normalized urine albumin and protein to creatinine (urine 
albumin/creatinine ratio, urine protein/creatinine ratio) over time will be generated. Corresponding 
summary figures will be generated as well. Urine albumin/creatinine ratio will be calculated as 1000 
* urine albumin (mg/dL) / urine creatinine (mg/dL), 
Shift tables of on-study urine albumin/creatinine ratio and urine protein/creatinine ratio will be 
generated with below ranges: 


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Urine Albumin/creatinine ratio 
Urine Protein/creatinine ratio 
< 30 mg/g 
< 150 mg/g 
30 to < 300 mg/g 
150 to < 500 mg/g 
>= 300 mg/g 
500 to < 1000 mg/g 
 
>= 1000 mg/g 
 
A listing for patients with ALT or AST > 3 x ULN will be generated to present all ALT, AST, Bilirubin, 
and ALP records from central and local lab.  
A listing will be provided for patients who terminated treatment due to a protocol-defined stopping 
rule (see Protocol section 8.6 for details) with categories (liver chemistry elevation, renal function 
test results, platelet count results) and narratives. 
3.5.5 
Exposure  
Treatment duration in days, number of injections of Study Drug, compliance to Study Drug, dose 
adjustment and dose interruption/pauses will be summarized for the safety set.  
• 
Treatment duration in days is defined as the last day on Study Drug minus the first day on Study 
Drug plus one. This will be derived for both index study period and the open-label study period. 
• 
Number of injections of Study Drug received includes those for which full volume of dose was 
not given. 
• 
Number of injections of Study Drug received for patients on active treatment in the index study 
will be the number of injections of Study Drug received from the first dose of the index study. 
Number of injections of Study Drug received for patients on placebo in the index study will be 
from the first dose of the open-label study. 
Treatment duration in months during index study and open-label study will be summarized for the 
safety set. 
• 
>=3 month category is defined as treatment duration in days >=85 days 
• 
>=6 month category is defined as treatment duration in days >=176 days 
• 
>=9 month category is defined as treatment duration in days >=267 days 
• 
>=12 month category is defined as treatment duration in days >=358 days 
• 
>=18 month category is defined as treatment duration in days >=541 days 
• 
>=24 month category is defined as treatment duration in days >=723 days 
Compliance to Study Drug will be summarized by descriptive statistics.  
• 
Compliance of the open-label study for Group 1, Group 2 and Group 3 will be calculated as 
follows:  
100 x (number of injections of Study Drug in the open-label study) / (number of injections 
scheduled during the Open-label Study Treatment Period).  


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• 
Compliance of the index study (ISIS 304801-CS6 or ISIS 304801-CS16) and open-label study 
overall for Group 1 and Group 2 will be calculated as follows:  
100 x (number of injections of Study Drug in the index study (ISIS 304801-CS6 or ISIS 
304801-CS16)+ number of injections of Study Drug in the open-label study) / (number of 
injections scheduled during the treatment period in the index study (ISIS 304801-CS6 or ISIS 
304801-CS16)+ number of injections scheduled during the treatment period in the open-
label study).  
3.5.6 
Physical Examination 
Adverse changes in physical examinations that are deemed clinically significant by the investigator 
will be classified as AEs. Physical examination results will be listed. 
3.5.7 
12-Lead Electrocardiogram 
ECGs will be performed in triplicate at the visits indicated in the protocol Schedule of Procedures. 
The ECG data will include ventricular rate, PR interval, QRS duration, QT and corrected QT intervals, 
and Overall interpretation.  For the continuous variables, the average of measurements at a given 
visit will be used for analysis. For overall interpretation, the worst categorical results of triplicate 
results and the associated findings will be used for analysis. For the continuous variables above, 
descriptive statistics (n, mean, standard error, standard deviation, median, 25th percentile, 75th 
percentile, minimum, and maximum) of the results, as well as the change from baseline to each 
study visit, will be presented by the group presented in Section 3.2.1 including overall in summary 
tables; for the categorical responses to overall interpretation, counts and percentages will be 
provided. 
All the data collected in triplicate will be listed. 
3.5.8 
Echocardiogram 
Echocardiogram results will be listed in a by patient data listing. 
3.5.9 
Concomitant Medications 
Medications start and stop dates that are recorded on the Prior and Concomitant Medications eCRF 
will be used to determine whether the medications are prior or concomitant to the treatment 
period.  Missing or partial dates will be imputed as outlined in section 3.5.1.2. Prior medications 
include medications started prior to Day 1 of Volanesorsen regardless whether continued while on 
treatment or not.  Concomitant medications include medications that patients exposed to on or 
after Day 1 of Volanesorsen. A prior medication with an imputed stop date that is missing or on or 
after date of Day 1 of Volanesorsen will also be considered as a concomitant medication. 
Medications will be classified based on (imputed) start and (imputed) stop dates as follows: 
1) Prior Medication 
Start Date 
End Date 


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< FDD 
Any non-missing stop date  
Missing 
2) Concomitant Medication  
Start Date 
End Date 
< FDD 
≥ FDD 
Missing 
≥ FDD  
Any non-missing stop date 
Missing 
CM = Concomitant Medication, FDD= Date of Day 1 of Volanesorsen, LDD= Date of Last Dose of Study Drug. 
Medication verbatim terms will be coded to Anatomical Therapeutic Chemical (ATC) classification 
and preferred name using the World Health Organization Drug Dictionary (version Sep 2016).   
Prior and concomitant medications will be summarized separately by ATC class, preferred name, 
treatment group and overall with counts and percentages for the Safety Set by sorting alphabetically 
and also by decreasing frequency in the overall column. Concomitant anti-coagulant and anti-
platelet medications will also be summarized for the Safety Set by decreasing frequency in the 
overall column. 
Additionally, medication changes during the on-treatment period which include those medications 
that are started, stopped, or changed dose during the on-treatment period (i.e. from Day 1 of 
Volanesorsen to the last dose of Study Drug + 28 days), will be summarized by ATC class, preferred 
name, treatment group and overall with counts and percentages for the Safety Set by sorting 
alphabetically and also by decreasing frequency in the overall column. 
Prior and concomitant medications will be displayed in patient data listings for all randomized 
patients.  Note that imputed dates will be used for prior and concomitant medications classification. 
Originally reported dates will be used for listings. 
3.5.10 MRIs 
MRI of the liver and spleen will be conducted at Week 52 for all patients for whom MRI is not 
contraindicated, e.g., patients having metal implants. The hepatic volume, splenic volume and 
hepatic fat will be summarized by the group presented in Section 3.2.1 . Change from baseline at 
Week 52 will be summarized as well. 
Liver and spleen MRIs will also be listed in a by-patient data listing.   


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4 
BIBLIOGRAPHY 
• 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007 
 


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