Clinical trial NCT03514420
Conditions: Familial Partial Lipodystrophy
Keywords: Lipodystrophy Lipodystrophy, Familial Partial Lipid Metabolism Disorders Dyslipidemias Kobberling-Dunnigan syndrome (type 1 and 2) Lipoatrophic Diabetes
Sponsor: Akcea Therapeutics
Start date: 2018-06-15; Completion date: 2019-08-21
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-center, open-label study to evaluate the efficacy of AKCEA-ANGPTL3-LRx for reduction of fasting triglycerides in participants with familial partial lipodystrophy.

Detailed description:

Arms: arm 1: Participants received AKCEA-ANGPTL3-LRx 20 milligrams (mg) administered every week for 26 weeks by subcutaneous (SC) injection.
Interventions: intervention 1: AKCEA-ANGPTL3-LRx
Intervention descriptions: intervention 1: AKCEA-ANGPTL3-LRx solution for SC injection.

Protocol documents:
Prot_SAP_000.pdf: 
 
           Official Title: 
 
An Open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
NCT Number: NCT03514420 
Document Dates: 
 
Original Protocol: 09-November-2017 
Protocol Amendment Version 1: 16-February-2018 
 
 
 


Clinical Study Report  
CONFIDENTIAL 
Study Number: ISIS 703802-CS5 
Akcea Therapeutics, Inc. 
14 Feb 2020 
16.1.1 
Protocol and Protocol Amendments 
Document included: 
•
Original Protocol, dated 09 Nov 2017
•
Protocol Amendment No. 1, dated 16 Feb 2018
•
Administrative Clarification Letter 1, dated 11 Sep 2018
•
Administrative Clarification Letter 2, dated 02 Oct 2018
•
Administrative Clarification Letter 3, dated 02 Jul 2019


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
1 
             
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010  
 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
 
 
 
ISIS 703802-CS5 
 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
 
Original Protocol – 09 November 2017 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
2 
 
 
 
ISIS 703802-CS05 
 
 
 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-
ANGPTL3-LRx) Administered Subcutaneously to Subjects 
with Familial Partial Lipodystrophy 
Original Protocol – 09 November 2017 
 
 
_________ 
, MD, FACP  
  
Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Telephone: (617) 207-0202 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
3 
 
ISIS 703802 
Ionis Protocol Number ISIS 703802-CS05 
Original Protocol  
 
Clinical Phase:  2 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-
LRx) Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Key sponsor contact:  
 
 - Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Phone: 
 
E-mail:
 
 Sponsor Medical Monitor: 
, MD 
- Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Phone: 
 
Mobile: 
 
E-mail:
 
 
Date: 
09 NOVEMBER 2017 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. and 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 Ionis 
Pharmaceuticals, Inc. and Akcea Therapeutics, Inc. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 703802-CS05 
Protocol Title: 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-
LRx) Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
 Amendment: 
Original Protocol 
Date:  
 
09 November 2017 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered 
Subcutaneously to Subjects with Familial Partial Lipodystrophy” dated 09 November 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. and Akcea Therapeutics, Inc. 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
5 
TABLE OF CONTENTS 
 
Page 
PROTOCOL SYNOPSIS ............................................................................................................. 9 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 15 
STUDY GLOSSARY .................................................................................................................. 16 
1. 
OBJECTIVES ................................................................................................................. 21 
1.1 
Primary Objective ..........................................................................................................21 
1.2 
Secondary Objective(s) ..................................................................................................21 
2. 
BACKGROUND AND RATIONALE .......................................................................... 21 
2.1 
Overview of Disease ......................................................................................................21 
2.2 
Therapeutic Rationale ....................................................................................................24 
2.3 
ISIS 703802 ...................................................................................................................25 
2.3.1 
Mechanism of Action .............................................................................................25 
2.3.2 
Chemistry ...............................................................................................................25 
2.3.3 
Preclinical Experience ............................................................................................26 
2.3.3.1 
Preclinical Pharmacology ................................................................................26 
2.3.3.2 
Preclinical Toxicology .....................................................................................27 
2.3.4 
Clinical Experience ................................................................................................28 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD ............................................................29 
2.4 
Rationale for Dose and Schedule of Administration .....................................................30 
2.5 
Benefit-Risk Assessment ...............................................................................................30 
2.5.2 
Risk Assessment .....................................................................................................30 
2.5.3 
Overall Assessment of Benefit: Risk ......................................................................31 
3. 
EXPERIMENTAL PLAN .............................................................................................. 32 
3.1 
Study Design ..................................................................................................................32 
3.2 
Number of Study Centers ..............................................................................................33 
3.3 
Number of Subjects .......................................................................................................33 
3.4 
Overall Study Duration and Follow-up .........................................................................33 
3.4.1 
Screening/Qualification ..........................................................................................33 
3.4.2 
Treatment ................................................................................................................33 
3.4.3 
Post-Treatment .......................................................................................................33 
4. 
SUBJECT ENROLLMENT ........................................................................................... 33 
4.1 
Screening .......................................................................................................................33 
4.2 
Registration ....................................................................................................................34 
4.3 
Replacement of Subjects ................................................................................................34 
5. 
SUBJECT ELIGIBILITY .............................................................................................. 34 
5.1 
Inclusion Criteria ...........................................................................................................34 
5.2 
Exclusion Criteria ..........................................................................................................36 
6. 
STUDY PROCEDURES ................................................................................................ 38 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
6 
6.1 
Study Schedule ..............................................................................................................38 
6.1.1 
Screening/Qualification ..........................................................................................38 
6.1.2 
Treatment Period ....................................................................................................38 
6.1.4 
Post-Treatment Period ............................................................................................39 
6.2 
Study/Laboratory Assessments ......................................................................................39 
6.2.1 
Physical Exams and Vital Signs .............................................................................40 
6.2.2 
DEXA Scan ............................................................................................................40 
6.2.3 
Electrocardiography ...............................................................................................40 
6.2.4 
PK Sampling ...........................................................................................................40 
6.2.5 
Mixed Meal Test ....................................................................................................41 
6.2.6 
MRI  
 ..................................................................................................................41 
6.3 
Restriction on the Lifestyle of Subjects .........................................................................41 
6.3.1 
Contraception Requirements ..................................................................................41 
6.3.2 
Other Requirements ................................................................................................42 
7. 
STUDY DRUG ................................................................................................................ 42 
7.1 
ISIS 703802 ............................................................................................................42 
7.2 
Packaging and Labeling .................................................................................................42 
7.3 
Study Drug Accountability ............................................................................................42 
8. 
TREATMENT OF SUBJECTS ..................................................................................... 43 
8.1 
Study Drug 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 Rules for Liver Chemistry Tests ..............................................44 
8.5.2 
Safety Monitoring for Renal Function ...................................................................45 
8.5.3 
Safety Monitoring Rules for Platelet Count Results ..............................................46 
8.5.4 
Safety Monitoring for Bleeding Events ..................................................................47 
8.5.5 
Safety Monitoring for Constitutional Symptoms ...................................................47 
8.5.6 
Safety Monitoring for Hypoglycemia ....................................................................47 
8.5.7 
Safety Monitoring for Documented Hyperglycemia ..............................................48 
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 / Temporary Stopping Rules for 
Renal Function Test Results ...................................................................................50 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................51 
8.7 
Adjustment of Dose and/or Treatment Schedule ...........................................................53 
8.8 
Discontinuation of Study Drug/Treatment ....................................................................54 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period ..........................................................................54 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
7 
8.9 
Withdrawal of Subjects 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 ..............................................................................................57 
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) ................................................................................57 
9.3.3.1 
Adverse Events of Special Interest ..................................................................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 Study Drug ........................................................................60 
9.4.3.4 
Treatment Given for Adverse Event ................................................................60 
9.4.3.5 
Outcome of the Adverse Event ........................................................................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 ............61 
9.5.3 
Dosing Errors .........................................................................................................61 
9.5.4 
Contraception and Pregnancy .................................................................................62 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 62 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................62 
10.1.1 
Primary Endpoint ...................................................................................................62 
10.1.2 
Secondary Endpoints ..............................................................................................62 
10.2 
Sample Size Considerations ...........................................................................................63 
10.3 
Populations .....................................................................................................................63 
10.4 
Definition of Baseline ....................................................................................................63 
10.5 
Interim Analysis and Early Stopping Guidelines ..........................................................63 
10.6 
Planned Methods of Analysis ........................................................................................63 
10.6.1 
Demographic and Baseline Characteristics ............................................................64 
10.6.2 
Safety Analysis .......................................................................................................64 
10.6.2.1 
Adverse Events ................................................................................................64 
10.6.2.2 
Clinical Laboratory Data..................................................................................64 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
8 
10.6.2.3 
Vital Signs and Examinations ..........................................................................64 
10.6.3 
Efficacy Analysis ...................................................................................................64 
10.6.4 
Pharmacokinetic Analysis ......................................................................................65 
10.6.5 
Pharmacodynamic Analysis ...................................................................................65 
10.6.6 
Additional Analyses ...............................................................................................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 .........................................66 
11.4 
Subject Confidentiality ..................................................................................................67 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 67 
12.1 
Protocol Amendments ....................................................................................................67 
12.2 
Study Termination .........................................................................................................67 
12.3 
Study Documentation and Storage ................................................................................67 
12.4 
Study Monitoring ...........................................................................................................68 
12.5 
Language ........................................................................................................................69 
12.6 
Compensation for Injury ................................................................................................69 
13. 
REFERENCES ................................................................................................................ 70 
14. 
APPENDICES ................................................................................................................. 73 
Appendix A 
Schedule of Procedures ....................................................................................74 
Appendix B 
List of Laboratory Analytes .............................................................................78 
Appendix C 
PK Sampling Schedule ....................................................................................80 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......82 
Appendix E 
Mixed Meal Test ..............................................................................................86 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ....................................................................................42 
Table 2 
Study Drug Dosing Information ............................................................................43 
Table 3 
Actions in Patients with Low Platelet Count .........................................................53 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  (MOE-
Gapmer).  The sequence of ISIS 703802 is shown. ...............................................26 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
9 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial Lipodystrophy 
Study Phase 
2 
Indication 
Familial Partial Lipodystrophy (FPL) 
Primary Objective 
To assess the effect of ISIS 703802 on reduction in fasting triglycerides (TG). 
Secondary Objectives 
To evaluate the safety and tolerability of ISIS 703802  
To evaluate the effect of ISIS 703802 on changes from Baseline to end of 
treatment on: 
• 
Plasma glucose, serum insulin, serum C-peptide and free fatty acid 
(FFA) in responses to a mixed meal test (MMT) 
• 
Lipids, lipoproteins and lipid metabolism 
• 
Glycosylated hemoglobin (HbA1c) 
• 
Liver fat and body fat distribution 
• 
Quality of life and pain score 
 
To evaluate pharmacokinetics (PK) of ISIS 703802  
Study Design 
This is a single-center, open-label study. 
The study will comprise the following periods: 
Screening period: Up to 6 weeks (including an up to 4 week run-in diet 
period) 
Treatment Period: 26 weeks  
Post-treatment Follow-up Period: 13 weeks 
The primary safety and efficacy analysis time point is at Week 27. 
Number of Subjects 
Approximately 3 
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 the time of informed consent   
3. 
Clinical diagnosis of familial partial lipodystrophy plus diagnosis of type 
2 diabetes mellitus and hypertriglyceridemia.  
Diagnosis of lipodystrophy is based on deficiency of subcutaneous 
body fat in a partial fashion assessed by physical examination and low 
skinfold thickness in anterior thigh by caliper measurement: men (≤ 10 
mm) and women (≤ 22 mm), and at least 1 of the following:  
- Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPAR-γ, 
AKT2, CIDEC, PLIN1 genes)  
OR 
- Family history of FPL or family history of abnormal and similar fat 
distribution plus 1 Minor Criteria  
OR 
- 2 Minor Criteria (In the absence of FPL-associated genetic variant or 
family history) and BMI< 35 kg/m2  
 
MINOR Criteria  


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
10 
a. 
Requirement for high doses of insulin, e.g., requiring ≥ 200 
U/day, ≥ 2 U/kg/day, or currently taking U-500 insulin  
b. 
Presence of acanthosis nigricans on physical examination  
c. 
Evidence/history of polycystic ovary syndrome (PCOS) or 
PCOS-like symptoms (hirsutism, oligomenorrhea, and/or 
polycystic ovaries)  
d. 
History of pancreatitis associated with hypertriglyceridemia  
e. 
Evidence of non-alcoholic fatty liver disease  
- Hepatomegaly and/or elevated transaminases in the 
absence of a known cause of liver disease or radiographic 
evidence of hepatic steatosis (e.g., on ultrasound or CT)  
4. 
A diagnosis of diabetes mellitus, made at least 6 months prior to the 
Screening, and:  
• A HbA1c ≥ 7% to ≤ 12% at Screening,  
• On anti-diabetic therapy consisting of:  
a. 
Metformin ≥ 1500 mg/day, or  
b. 
If the dose of metformin is < 1500 mg/day, or metformin is 
not tolerated, then the patient should be on other oral anti-
diabetic drugs (OAD) or an injectable glucagon-like peptide-1 
(GLP-1) receptor agonist, or  
c. 
Insulin therapy alone or in combination with other anti-
diabetic drugs 
5. 
Hypertriglyceridemia as defined by Fasting TG levels ≥ 500 mg/dL (≥ 
5.7 mmol/L) at both Screening and Qualification visits. Patients with the 
clinical diagnosis of FPL and with Fasting TG levels ≥ 200 (≥ 2.26 
mmol/L) to < 500 mg/dL (≥ 5.7 mmol/L) at both Screening and 
Qualification Visits who meet the genetic or family history criteria for 
study inclusion may be further screened and enrolled in the study 
 
6. 
Presence of hepatosteatosis (fatty liver), as evidenced by a Screening 
MRI indicating a hepatic fat fraction (HFF) ≥ 6.4% 
 
7. 
Willing to maintain their customary physical activity level and to follow a 
diet moderate in carbohydrates and fats with a focus on complex 
carbohydrates and replacing saturated for unsaturated fats 
 
8. 
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 at least 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 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
11 
utilizing an acceptable contraceptive method (refer to Section 
6.3.1) from the time of signing the informed consent form until at 
least 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. 
A diagnosis of generalized lipodystrophy 
2. 
A diagnosis of acquired partial lipodystrophy (APL) 
3. 
Acute pancreatitis within 4 weeks of 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 heart 
failure requiring a change in medication 
5. 
Major surgery within 3 months of Screening  
6. 
History of heart failure with New York Heart Association functional 
classification (NYHA) greater than Class II or unstable congestive 
cardiac failure requiring a change in medication 
7. 
Uncontrolled hypertension (blood pressure [BP] > 160 mm Hg systolic 
and/or 100 mm Hg diastolic) 
8. 
Clinically-significant abnormalities in screening laboratory values that 
would render a subject unsuitable for inclusion, including the following: 
a. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event 
of a UPCR above this threshold, eligibility may be confirmed by a 
quantitative total urine protein measurement of ˂ 1 g/24-hr 
b. Estimated GFR ˂ 60 mL/min (as determined by the Chronic 
Kidney 
Disease-Epidemiological 
Collaboration 
(CKD-EPI) 
Equation for creatinine clearance 
c. Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 2x ULN 
d. Bilirubin > ULN, unless prior diagnosis and documentation of 
Gilbert’s syndrome in which case total bilirubin must be ≤ 3 mg/dL 
e. Alkaline phosphatase (ALP) > 1.5 X ULN 
f. Platelet count ˂ LLN 
9. 
Uncontrolled hyper- or hypothyroidism.  Subjects on dose stable 
replacement therapy for at least 3 months prior to Screening will be 
allowed 
10. History within 6 months of Screening of drug or alcohol abuse 
11. History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
12. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
13. Known history of or positive test for human immunodeficiency virus 
(HIV), hepatitis C or chronic hepatitis B 
14. Malignancy within 5 years, except for basal or squamous cell 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
12 
carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated 
15. Treatment with another investigational drug, biological agent, or device 
within 1-month of Screening, or 5 half-lives of investigational agent, 
whichever is longer 
16. Unwilling to comply with lifestyle requirements (see Section 6.3) 
17. Use of any of the following: 
a. 
Metreleptin within the last 3 months prior to Screening 
b. 
Antidiabetic, lipid lowering, or atypical antipsychotic medication, 
unless on a stable dose for at least 3 months prior to Screening.  
For lipid lowering medications (e.g., omega-3 fatty acids) dose, 
brand and regimen are expected to remain the same from Day 1 
throughout Week 13.  Patients not receiving these drugs within 4 
weeks prior to Screening are also eligible 
c. 
Insulin unless on a stable daily basal insulin dose regimen (± 20 
%) for at least 4 weeks prior to dosing 
d. 
GLP-1 agonists within 4 weeks prior to dosing, if patient has a 
history of pancreatitis 
e. 
Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior 
to Screening 
f. 
Systemic corticosteroids or anabolic steroids within 6 weeks prior 
to Screening unless approved by the Sponsor Medical Monitor 
g. 
Antihypertensive medication unless on a stable dose for at least 4 
weeks prior to dosing 
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 throughout the study 
i. 
Oral anticoagulants unless on a stable dose for at least 4 weeks 
prior to dosing and regular clinical monitoring is performed 
j. 
Anti-obesity drugs [e.g., the combination of phentermine and 
extended-release topiramate (Qsymia), orlistat (Xenical), and 
lorcaserin (Belviq), phentermine, amphetamines, herbal 
preparations] within 12 weeks prior to Screening (except 
liraglutide [rDNA origin] injection (Saxenda) if on stable therapy 
for more than 6 weeks prior to Screening). 
k. 
Any other medication unless stable at least 4 weeks prior to 
dosing (occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
18. Blood donation of 50 to 499 mL within 30 days of Screening or of          
> 499 mL within 60 days of Screening 
19. 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 Groups 
Single Group, open-label treatment with 20 mg of ISIS 703802 SC weekly 
Study Drug Dosage and 
Administration 
The Sponsor will provide ISIS 703802 in a single vial with a concentration of 
100 mg/mL 20 mg every week of ISIS 703802 (0.2 mL).  
The study dose of 20 mg (0.2 mL) of ISIS 703802 will be administered every 
week during the treatment period for a total of 26 weekly doses.  
All doses will be given by SC injection.  Self-administration will be allowed 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
13 
after appropriate training of subject and/or caregiver. 
Rationale for Dose and Schedule 
Selection 
A 20 mg weekly dose was selected as being the lowest dose that provided 
maximum TG lowering of approximately 60%, based on the TG lowering 
effect of ISIS 703802 observed in healthy volunteers with elevated TGs. 
Adjustment of Dose or Treatment 
Schedule 
Dose adjustments, including dose interruptions, and/or decreasing the dose 
and dose frequency may be allowed for safety or tolerability after consultation 
with the Sponsor Medical Monitor.   
Study Visit Schedule and 
Procedures 
Detailed information regarding the study procedures are outlined in Section 6, 
Appendices A and C. 
The study for an individual subject will generally consist of the following 
periods:  
• 
An up to 6-week Screening period, including a 4-week diet 
stabilization phase for subjects not already on a stable diet 
• 
A 26-week treatment period during which Study Drug will be 
administered weekly by SC injection 
• 
A 13-week post-treatment follow-up period 
During the Screening period, subject will be advised to maintain diet and 
exercise routines, and remain on a stable regimen of diabetes and lipid 
medications (if they are already taking any).  As part of the Screening period, 
subjects may have 4 weeks of diet run-in and final eligibility will be 
determined during qualification.  Subjects on stable diet known to the 
investigator and followed at the site may go from Screening to qualification 
without a 4-week diet run-in. TGs will be measured and MRI will be obtained 
to assess liver fat content.  For subjects who are already on a stable diet and 
are known to the site, the diet stabilization period can be omitted and subject 
can move directly to qualification. 
Subjects meeting eligibility criteria at Screening and having a qualifying MRI, 
defined as having at least 6.4% liver fat assessed by MRI-PDFF (via central 
reviewer) will return to the clinic on Day 1.  In addition, TG will be measured 
at qualification and results of TG and MRI must be available prior to 
registration and administration of the first dose of study drug. 
Blood and urine samples will be collected regularly throughout the study for 
safety, efficacy, and PK analysis.  Appendix B shows a list of analytes 
required for the study and Appendix C details the PK sample schedules. 
The Mixed Meal Test (MMT) will be done at Baseline, at week 13 and at week 
27.  This test consists of having the subject consume a standardized meal in 
the evening and fast overnight for at least 8 hours.  The following morning, 
before the test, fasting plasma glucose, free fatty acids (FFA), C-peptide, 
insulin, serum ghrelin, GIP, GLP-1 and PYY as well as incretin hormones are 
measured.  The subject then consumes a liquid standard meal (such as 
Optifast®) and the same metabolic parameters are measured again over the 
course of 300 minutes at 10, 20, 30, 60, 90, 120, 150, 180, 240 and 300 
minutes.  In addition, a validated visual analogue scale (VAS) will be used to 
measure the subject’s perception of hunger. 
Safety and Tolerability 
Evaluations 
Safety and tolerability assessments include: AEs, vital signs and weight, 
physical examinations, clinical laboratory tests, ECGs, use of concomitant 
medications.   


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
14 
Efficacy Evaluations 
Primary Endpoint:  
• 
The effect of ISIS 703802 on the percent change from Baseline in 
fasting triglyceride levels (TG) at week 27 
Secondary Endpoints: 
• 
Change from Baseline in AUC plasma glucose, serum insulin, serum 
C-peptide, free fatty acid, serum ghrelin, GIP, GLP-1, and PYY in 
response to a mixed meal test (MMT) 
• 
Change from Baseline in lipids and lipoproteins including high-
density lipoprotein cholesterol (HDL-C), low-density lipoprotein 
cholesterol (LDL-C), total cholesterol (TC), very low-density 
lipoprotein cholesterol (VLDL-C), non-HDL-C, apolipoprotein B 
(apoB), apolipoprotein B-48 (apoB-48), apolipoprotein B-100 (apoB-
100), apolipoprotein A-1 (apoA-1), apolipoprotein C-III (apoC-III: 
total, chylomicron, VLDL, LDL and HDL), Lipoprotein a [Lp(a)], free 
fatty acids (FFA), and glycerol levels, lipoprotein particle 
size/number 
• 
Change from Baseline in glycosylated hemoglobin (HbA1c) 
• 
Change from Baseline in homeostasis model assessment-estimated 
insulin resistance (HOMA-IR) 
• 
Change from Baseline in adiponectin and leptin 
• 
Change from Baseline in hepatic fat fraction (as assessed by 
magnetic resonance imaging [MRI]) 
• 
Changes from Baseline in body fat distribution for various areas in 
the body as measured by skinfold thickness and dual-energy X-ray 
absorptiometry (DEXA); visceral adipose tissue (VAT) and 
subcutaneous adipose tissue (SAT) as measured by MRI; body 
weight, waist circumference and waist/hip ratio 
• 
Changes from Baseline in quality of life and pain score 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
ISIS 703802 trough levels throughout treatment and levels during the post-
treatment Follow-up period.  Plasma sample collection time points are 
detailed in Appendix A and Appendix C. 
Pharmacodynamic Evaluations 
Plasma angiopoietin-like 3 (ANGPTL3), HDL-C, LDL-C, TC, VLDL-C, non-
HDL-C, apoB, apoB-48, apoB-100, apoA-1, apoC-III, Lp(a), FFA, glycerol 
levels, lipoprotein particle size/number 
Statistical Considerations 
There is no statistical rationale for the selected sample size.   
Sponsor/Collaborator 
Ionis Pharmaceuticals, Inc./ Akcea Therapeutics, Inc. 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
09 November 2017 
15 
STUDY DESIGN AND TREATMENT SCHEMA 
TREATMENT PERIOD
Weeks 1 to 26 
All Subjects will be receive 20 mg of ISIS 
703802 administered weekly by SC injection
Dosing, routine safety assessments, PK and 
PD/efficacy assessment at specified time 
points 
POST-TREATMENT 
EVALUATIONS
Week 4, 8 and 13 post-treatment 
3 clinical visits for safety, PK and PD 
assessments 
END-OF-STUDY 
PROCEDURES 
Early termination or 13 
weeks after last dose of 
Study Drug
EARLY 
TERMINATION
(ET) 
Follow ET visit in 
Schedule of 
Procedures 
Patient strongly 
encouraged to visit 
clinic for post-
treatment 
SCREEN PERIOD / DIET RUN-IN 
Weeks -6 to -1 
(Period may be reduced if the patient is 
following a stable low fat diet for a minimum of 4 
weeks) 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
16 
STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANA 
antinuclear antibody 
ANGPTL3 
Angiopoietin-like 3 
APL 
Acquired Partial Lipodystrophy 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
ASGPR 
Asialoglycoprotein Receptor 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the curve 
AUCt 
area under the plasma concentration-time curve from time 
zero to time t 
Bb 
complement factor Bb (activated complement split product) 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy 
test) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
centigrade 
C5a 
complement factor C5a (activated complement split product) 
Cmax 
maximum concentration 
CBC 
complete blood count 
CKD-EPI 
Chronic Kidney Disease Epidemiological Collaboration 
CL 
systemic clearance 
CMV 
Cytomegalovirus 
CRF 
case report form 
CRNMB 
Clinically-relevant Non-major Bleeding 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
17 
CS 
clinically significant 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTM 
Clinical Trial Manager 
DEXA 
dual-energy X-ray absorptiometry 
dL 
deciliter 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
End of Treatment 
FFA 
Free Fatty Acid 
FHBL2 
Familial combined hypolipidemia 
FPG 
Fasting Plasma Glucose 
FPL 
Familial Partial Lipodystrophy 
FSH 
follicle-stimulating hormone 
g 
gram 
GalNAc 
N-acetyl galactosamine  
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GIP 
Gastric Inhibitory Polypeptide 
GLP-1 
Glucagon-like Peptide 1 
HAV 
hepatitis A virus 
Hb 
Hemoglobin 
HBA1c 
Glycosylated hemoglobin 
HBsAg 
hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
hepatitis C virus 
HDL 
High Density Lipoprotein 
HFF 
Hepatic Fat Fraction 
HIPAA 
Health Insurance Portability and Accountability Act 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
18 
HIV 
human immunodeficiency virus 
HOMA-IR 
Homeostasis Model Assessment-estimated Insulin Resistance 
HR 
heart rate 
hr, hrs 
hour(s) 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon-gamma 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1 beta 
IL-6 
interleukin-6 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 703802 
antisense inhibitor of ANGPTL3 
IV 
Intravenous(ly) 
kg 
kilogram 
L 
liter 
LDL-C 
Low Density Lipoprotein Cholesterol 
LPL 
Lipoprotein Lipase 
m2 
square meter 
MAD 
multiple ascending dose 
MB 
Major Bleeding 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
mg 
milligram 
min 
minute 
mL 
milliliter 
mm 
millimeter 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
19 
MMT 
Mixed Meal Test 
MTD 
maximum tolerated dose 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NEFA 
Non-esterified Fatty Acids 
NOAEL 
No Adverse Effect Level 
NCS 
not clinically significant 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
on study 
The insert [subject] or [patient] is ‘on study’ from signing of 
the informed consent until their last study visit 
OAD 
Oral Antidiabetic Drugs 
OTC 
Over the Counter 
PCOS 
Polycystic OvarySyndrome 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PLT 
Platelet  
pRBC 
packed red blood cells 
PT 
prothrombin time 
PYY 
Peptide Tyrosine Tyrosine 
RBC 
Red Blood Cells 
REMS 
Risk Evaluation ad Mitigation Strategy 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the 
RNA strand in RNA/DNA hybrids 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAT 
Subcutaneous Adipose Tissue 
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
SMBG 
Self Monitored Blood Glucose 
Study Day 1 
defined as the first day Study Drug product is administered 
to the patient 
Study Drug 
ISIS 703802  


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
20 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TG 
Triglycerides 
Tmax 
time to maximal concentration 
TNF-α 
tumor necrosis factor-alpha 
T2DM 
Type 2 Diabetes 
ULN 
upper limit of normal 
UACR 
Urine albumin/creatinine ratio 
UPCR 
Urine Protein Creatinine Ratio 
VAT 
Visceral Adipose Tissue 
VLDL 
Very Low Density Lipoprotein 
WBC 
white blood cell 
WMA 
World Medical Association 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
21 
1. 
OBJECTIVES 
1.1 
Primary Objective 
The primary objective of this study is to assess the effect of ISIS 703802 on reduction in fasting 
triglycerides (TG). 
1.2 
Secondary Objective(s) 
The secondary objectives are: 
• To evaluate the safety and tolerability of ISIS 703802  
• To evaluate the effect of ISIS 703802 on changes from Baseline to end of treatment on: 
o Plasma glucose, serum insulin, serum C-peptide and free fatty acid (FFA) in 
responses to a mixed meal test (MMT) 
o Lipids, lipoproteins and lipid metabolism 
o Glycosylated hemoglobin (HbA1c) 
o Liver fat and body fat distribution 
o Quality of life and pain score 
• To evaluate pharmacokinetics (PK) of ISIS 703802. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Lipodystrophy syndromes are a group of rare metabolic diseases characterized by selective loss 
of adipose tissue that leads to ectopic fat deposition in liver and muscle and the development of 
insulin resistance, diabetes, dyslipidemia and fatty liver disease (Garg 2004; Chan and Oral 
2010; Garg et al. 2011; Shulman et al. 2014). 
These syndromes are categorized according to the distribution of fat loss into generalized or 
partial and according to the underlying etiology as inherited or acquired (Garg 2004; Chan and 
Oral 2010; Garg et al. 2011). 
These syndromes constitute a significant medical unmet need as these patients are refractory to 
current therapies, mainly used to treat diabetes and elevated TG levels, in an attempt to reduce 
the risk of serious associated complications (coronary artery disease, diabetic nephropathy, 
cirrhosis and pancreatitis). 
As such, in February 2014, the FDA approved Myalept (metreleptin) as replacement therapy to 
treat the complications of leptin deficiency in addition to diet in patients with congenital or 
acquired generalized lipodystrophy.  The safety and effectiveness of Myalept was evaluated in 
2 open-label studies conducted at the NIH, which included 72 patients (48 with generalized 
lipodystrophy and 24 with partial lipodystrophy [PL]) with diabetes, high TG, and elevated 
levels of fasting insulin.  The best results were achieved in patients with generalized 
lipodystrophy who had low leptin levels (mean [SD]: 1.3 [1.1] ng/mL), while patients with 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
22 
partial lipodystrophy who had a wider range of baseline leptin values (mean [SD]: 4.9 
[3.1] ng/mL) had a more varied and attenuated response.  Because of the risks associated with 
the development of neutralizing antibodies and lymphoma, Myalept is available only through a 
risk evaluation and mitigation strategy (REMS) program, which requires prescriber and 
pharmacy certification and special documentation (Chan et al. 2011; Myalept PI). 
At the present time, the Sponsor does not intend to study the generalized forms for which a 
specific therapy exists (metreleptin) nor the acquired forms of the partial lipodystrophy disorders 
because of the heterogeneity of etiologies, some iatrogenic, and the high incidence of associated 
immune disorders in these populations.  Therefore, this study will focus only on patients with the 
congenital form of the partial lipodystrophy disorders and, among those, on the most severe 
subtype, patients with familial partial lipodystrophy, or FPL.  
Familial Partial Lipodystrophy (FPL) is an orphan disease for which no specific pharmacologic 
treatment currently exists.  FPL was described in the 1970s independently by Köbberling and 
Dunnigan (Dunnigan et al. 1974; Köbberling et al. 1975), and is the most common subtype of 
inherited PL (National Organization for Rare Disorders [NORD] 2012).  It has been estimated 
that FPL affects approximately 0.2 in 10,000 people in the European Union, which is equivalent 
to a total of around 10,000 people (Committee for Orphan Medicinal Products 2012).  FPL 
encompasses several subtypes differentiated by the underlying genetic mutation (6 FPL subtypes 
and mutations in 5 genes have been identified).  FPL type 1, Köbberling variety has been 
reported in a handful of individuals and its molecular basis is unknown.  FPL type 2, Dunnigan 
variety is the most common form and the most well characterized disorder and is due to missense 
mutations in the A and C LMNA gene.  FPL type 3 has been reported in 30 patients and is due to 
mutations in the PPARg gene.  FPL type 4 has been reported in 5 patients and is due to mutations 
in the PLIN1 gene.  FPL type 5 has been reported in 4 members of a family who presented with 
insulin resistance and diabetes and is due to mutations in the AKT2 gene.  The last subtype, 
Autosomal Recessive FPL has been identified recently in 1 patient with homozygous mutations 
in CIDEC.  Some individuals with FPL do not have mutations in any of these genes, suggesting 
that additional, as yet unidentified genes can cause the disorder (Hegele et al. 2007; Garg et al. 
2011; National Organization for Rare Disorders [NORD] 2012). 
The diagnosis of FPL is mainly clinical and needs to be considered in patients presenting with 
the triad of insulin resistance (with or without overt diabetes), significant dyslipidemia in the 
form of hypertriglyceridemia, and fatty liver (Huang-Doran et al. 2010).  Patients often present 
with diabetes and severe insulin resistance requiring high doses of insulin.  Other evidence of 
severe insulin resistance is provided by the presence of acanthosis nigricans and polycystic ovary 
syndrome (PCOS) (with symptoms like hyperandrogenism and oligomenorrhea).  Some patients 
develop severe hypertriglyceridemia resulting in episodes of pancreatitis.  In many patients, the 
TG levels remain persistently elevated despite fully optimized therapy or diet modifications.  
Radiographic evidence of hepatic steatosis or steatohepatitis with hepatomegaly and/or elevated 
transaminases is common (Handelsman et al. 2013).  Patients with the Dunnigan variety have a 
higher risk of coronary artery disease (Hegele 2001).  Although very rare, patients with a specific 
mutation in the LMNA gene are at an increased risk of cardiomyopathy and its associated 
complications, congestive heart failure and conduction defects. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
23 
There is limited natural history data, mostly cross-sectional and derived from publication of 
baseline characteristics of patients entering a clinical trial (Diker-Cohen CE et al. 2015; Ajluni N 
et al. 2016; Akinci B et al. 2017; Ahmed Z et al. 2013; Bidault G. et al. 2013).  The evidence that 
FPL progresses over time comes from a prospective, open-label NIH study with ongoing 
enrollment since 2000 (N = 87).  Data analyzed in 2014 showed that metabolic manifestations of 
the cohort of 32 partial lipodystrophy patients (including 25 FPL) were as severe as those of the 
cohort of generalized lipodystrophy (N = 55), which is recognized as a more severe form of 
lipodystrophy (Diker-Cohen CE et al. 2015).  
Patients with FPL have both a partial loss and maldistribution of adipose tissue leading to their 
distinct phenotype.  In many of these patients mutations in proteins involved in adipocyte 
differentiation, fatty acid uptake by adipocytes, triglyceride synthesis, or lipid droplet formation 
have been identified (Garg et al. 2011, Handelsman et al. 2013).  Due to this severe dysfunction 
of adipose tissue FPL patients have much lower TG storage capacity than patients with 
hypertriglyceridemia without FPL, highlighting the importance of TGs in the pathophysiology of 
FPL.  Plasma TG levels in FPL patients varied across studies from mean (25-75 percentile) 483 
mg/dL (232, 856) (Diker-Cohen CE et al. 2015), median (25-75 percentile) 342 mg/dL (279, 
801) (Akinci B et al. 2017), mean 383 mg/dL (Bidault G et al. 2013), median 389 mg/dL (155-
3455) (Ahmed Z et al. 2013) and mean 1058 mg/dL (Ajluni N et al. 2016).  It is estimated that 
1/4 to 1/5 of patients with FPL may have TG levels > 500 mg/dL. 
Due to inability of adipose tissue to accommodate excess TGs, TGs are deposited in higher 
amounts in organs other than adipose tissue that are less well adapted to excess lipid storage 
(“ectopic fat”) (Garg et al. 2011, Handelsman et al. 2013; Robbins et al. 2015; Nolis 2014; 
Huang-Doram et al. 2010). This ectopic fat accumulation has been found in and around many 
organs and is most clearly associated with metabolic abnormalities in the liver, pancreas and 
skeletal muscle contributing to severe insulin resistance, hepatic steatosis, diabetes and 
hypertriglyceridemia and increased risk of pancreatitis, non-alcoholic steatohepatitis and 
cirrhosis (Robbins et al. 2015; Nolis 2014; Huang-Doram et al. 2010; Vatier et al. 2013; Sleigh 
A et al. 2012). 
Careful clinical assessment of fat distribution through visual and physical examination can 
confirm the diagnosis.  Patients with FPL have reduced subcutaneous fat in the limbs and truncal 
regions and may have excess subcutaneous fat deposition in neck, face and intra-abdominal 
regions.  Patients with the Dunnigan variety have normal body fat distribution in childhood and 
gradually lose subcutaneous fat from the extremities and trunk around the time of puberty.  In 
women, the loss of fat may be most striking in the buttocks and hips.  At the same time these 
patients accumulate fat on the face (“double chin”), neck and upper back (“Cushingoid 
appearance with buffalo hump”).  The extent of adipose tissue loss usually determines the 
severity of the metabolic abnormalities.  Patients display prominent muscularity and 
phlebomegaly (enlarged veins) in the extremities and complain of disproportionate hyperphagia.  
The condition in females is more easily recognized than in men, and so is reported more often.  
Patients may also have a family history of similar physical appearance and/or fat loss. 
Genetic testing, when available, is confirmatory. (Hegele et al. 2007; Huang-Doram et al. 2010; 
Garg et al. 2011). 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
24 
Current treatment includes lifestyle modification such as reducing caloric intake and increasing 
energy expenditure via exercise.  Conventional therapies used to treat severe insulin resistance 
(metformin, thiazolidinediones, Glucagon-like peptide 1s [GLP-1], insulin), and/or high TGs 
(dietary fat restriction, fibrates, fish oils) are not very efficacious in these patients (Chan and 
Oral 2010). 
Familial Partial Lipodystrophy is an ultra-orphan indication for which there is a significant 
unmet medical need.  Diabetes, hepatic steatosis, and hypertriglyceridemia associated with this 
condition can lead to serious complications (Handelsman et al. 2013) such as: 
• Acute pancreatitis, especially when triglyceride levels are > 1,000 mg/dL 
• Accelerated microvascular complications from uncontrolled diabetes 
• Accelerated cardiovascular disease from lipid abnormalities and insulin resistance 
• Steatohepatitis that can progress to cirrhosis and an increased risk of hepatocellular 
carcinoma 
• Proteinuric nephropathies which can progress to end stage renal disease 
In patients with Generalized Lipodystrophy the metabolic complications are partially related to 
leptin deficiency, and can be ameliorated in part by leptin replacement.  However, leptin 
deficiency alone cannot explain the severity of metabolic disease in patients with PL who have 
variable leptin levels.   
By reducing ANGPTL3 and TG levels, ISIS 703802 may improve the metabolic profile of 
patients with FPL and reduce their risk of acute pancreatitis.  In addition, reductions in TG could 
improve hepatic steatosis and reduce cirrhosis risk. Furthermore, this mechanism may also 
improve insulin sensitivity in these patients and potentially lead to a reduction in the 
complications associated with diabetes.   
2.2 
Therapeutic Rationale 
In humans, loss of function mutations within the ANGPTL3 gene give rise to familial combined 
hypolipidemia (FHBL2), characterized by low plasma levels of triglycerides, total cholesterol, 
LDL-C, and HDL-C (Minicocci et al. 2012).  Homozygous individuals with complete 
ANGPTL3 deficiency showed the full combined hypolipidemic phenotype while individuals 
with more partial ANGPTL3 deficiency showed a more attenuated phenotype.  Of note, FHBL2 
homozygous were not affected by diabetes, showed lower plasma levels of insulin and lower 
degree of insulin resistance as estimated by HOMA-IR (Robciuc et al. 2013).   
ANGPTL3 protein is produced exclusively in liver, where its expression is downregulated by 
leptin and insulin (Inukai et al. 2004).  Hepatic specific knock-down of ANGPTL3 mRNA is 
associated with reduction in plasma triglycerides due to increased lipoprotein lipase activity as 
well as decreased hepatic VLDL triglyceride secretion.  Because ANGPTL3 is produced by the 
liver only, which does not express LPL, it is thought to function as an endocrine rather than 
paracrine factor with insulin sensitizing effects that go beyond the liver.  In fact, insulin 
sensitization has been shown in patients with ANGPTL3 gene mutations as well as in 
ANGPTL3-deficient mice, in which increased uptake of fatty acids into oxidative tissues such as 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
25 
muscle and brown adipose tissue led to decreased uptake of fatty acids and increased uptake of 
glucose in white adipose tissue (Wang et al. 2015).  Suppression of hepatic ANGPTL3 protein 
production in mice resulted in significant reductions in levels of triglycerides, LDL cholesterol, 
non-HDL cholesterol, and VLDL cholesterol and these favorable effects were associated with 
decreased liver triglyceride content, increases in insulin sensitivity, and a reduction in 
atherosclerosis progression (Graham et al. 2017).    
Treatment with ISIS 703802 would be expected to lower the hepatic expression of ANGPTL3 
protein and result in lowering of the levels of triglyceride-rich lipoproteins and LDL-C, increased 
HDL-C, improved glycemic control and ameliorated insulin resistance in T2DM patients, 
leading to decreased liver fat content in NAFLD and ultimately, reduced overall risk of coronary 
artery disease.  
2.3 
ISIS 703802 
2.3.1 
Mechanism of Action 
ISIS 703802 is a second-generation ASO drug targeted to ANGPTL3 that has been covalently 
bonded to triantennary N-acetyl galactosamine (GalNAc), a high-affinity ligand for the 
hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc conjugate.  
This GalNAc-conjugate approach results in enhanced ASO delivery to hepatocytes versus 
non-parenchymal cells and has increased ASO potency by approximately 10-fold in mice 
(Prakash et al. 2014).  The ASO portion of ISIS 703802 is complementary to a region within the 
ANGPTL3 messenger ribonucleic acid (RNA) (mRNA) coding sequence, and binds to the 
mRNA via Watson and Crick base pairing.  The hybridization (binding) of ISIS 703802 to the 
cognate mRNA results in the Ribonuclease H1 (RNase H1)-mediated degradation of the 
ANGPTL3 mRNA, thus preventing production of the ANGPTL3 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, ISIS 703802 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate and phosphodiester linkages (mixed backbone 
design).  The mixed backbone design reduces the total number of phosphorothioate linkages in 
the MOE-modified regions, which reduces non-specific interactions with proteins and further 
enhances potency of GalNAc conjugated ASOs.  The nucleotide sequence of ISIS 703802 
(Figure 1) is complementary to a 20-nucleotide stretch within Exon 6 of the ANGPTL3 mRNA 
coding sequence at position 1169-1188 bp. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end 
and the 5 nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified 
ribonucleotides.  These MOE-modified nucleotides confer (1) increased affinity for 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 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
26 
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 ISIS 703802 
employs this chimeric structure to enable use of the RNase H1 mechanism for antisense activity.  
This is because while the 2′-MOE modification confers increased stability and affinity, it does 
not support RNase H1 catalyzed cleavage of RNA hybridized to 2′-MOE-modified nucleotides 
(McKay et al. 1999).  This is caused by conformational changes induced in the heteroduplex by 
2′-alkoxy:RNA hybrids that are not recognized by RNase H enzymes (Inoue et al. 1987; Monia 
et al. 1993).  By limiting the 2′-MOE modification to nucleotides flanking the phosphorothioate 
oligodeoxynucleotide core, the beneficial attributes of the 2′-MOE chemistry are preserved while 
also retaining RNase H1 recognition.  The fourth region is comprised of a triantennary cluster of 
N-acetyl galactosamine (GalNAc) sugars which is linked to the 5ʹ end of ISIS 703802 via a 
phosphodiester linkage.  The GalNAc cluster is a high affinity ligand for the asialoglycoprotein 
receptor (ASGPR), a receptor expressed primarily on the surface of liver hepatocytes (Stockert 
1995).  The GalNAc cluster enhances delivery of ISIS 703802 to liver hepatocytes over other 
cell types and enhances potency.  After internalization into cells, the GalNAc cluster is 
metabolized to release ‘free ASO’ inside the cell (Prakash et al. 2014). 
 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of ISIS 703802 is shown. 
2.3.3 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ANGPTL3 ASOs can be 
found in the Investigator’s Brochure.  A summary is included below. 
2.3.3.1 
Preclinical Pharmacology 
The pharmacology of ANGPTL3 ASOs has been examined in multiple in vitro cell lines where 
specific and dose-dependent reduction of ANGPTL3 mRNA and protein was clearly 
demonstrated, resulting in reductions in apoB secreted protein.  The pharmacology of 
ISIS 563580, an unconjugated 2′-MOE modified ASO that has the same base sequence as ISIS 
703802, at doses higher than planned for ISIS 703802. 
2ʹ-MOE 
2ʹ-MOE 
2ʹ-Deoxy 
GalNAc = THA-GalNAc cluster 
2ʹ-MOE = 2ʹ-methoxylethyl 
RNA 
2ʹ-Deoxy = DNA 
s = phosphorothioate linkage 
o = phosphodiester linkage 
(RNase H1 sensitive) 
GalNAc 
GsGoAoCoAo 
TsTsGsCsCsAsGsTsAsAs 
ToCoGsCsA 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
27 
ISIS 563580 has been explored in human ANGPTL3 transgenic mice, wherein liver mRNA and 
plasma ANGPTL3 protein levels were reduced upon treatment with ISIS 563580. 
Reductions in murine ANGPTL3 mRNA and protein were routinely observed in all mouse 
models treated with a murine-specific ANGPTL3 ASO.  Pharmacology studies were done with 
Ldlr-/- mice fed a hypercholesterolemic diet known to develop elevated LDL-C, TG, and 
atherosclerosis, as well as features of metabolic syndrome (hyperglycemia and hyperinsulinemia) 
(Huszar et al. 2000; Schreyer et al. 2002; Tsuchiya et al. 2012).  Treatment of mice with a 
murine-specific ANGPTL3 ASO resulted in improvement in all of the aforementioned lipid and 
metabolic endpoints compared to controls.  In all mouse models tested, total plasma cholesterol, 
LDL-C, TG, and non-esterified fatty acids (NEFA) have been shown to be consistently reduced 
upon treatment with ANGPTL3 ASOs, while HDL-C is modestly decreased in wild type mice 
(- 22%), and either stable or increased in others.  While a clear mechanistic understanding of 
HDL-C reductions has not been elucidated, results from in vitro reverse cholesterol transport 
assays suggest that HDL function is maintained. 
Administration of ISIS 703802, a human specific, GalNAc conjugated, ANGPTL3 ASO, to 
human ANGPTL3 transgenic mice led to significant, dose-dependent reductions in hepatic 
ANGPTL3 mRNA.  In diet challenged mice, administration of ISIS 731875, a mouse-specific 
and GalNAc-modified ASO targeting ANGPTL3, led to dose-dependent reductions in both 
hepatic ANGPTL3 mRNA and plasma ANGPTL3 with concomitant reductions in plasma TG 
and cholesterol.  Importantly, the potency and the lipid-lowering effects of the ANGPTL3 ASO 
were independent of diet. 
Finally, administration of a mouse-specific ANGPTL3 ASO to western diet fed Ldlr-/-, a mouse 
model of FH, also led to significant reductions in hepatic ANGPTL3 mRNA and plasma 
ANGPTL3 protein with concomitant reductions in plasma TG and LDL-C that were similar to 
what was observed in wild type western diet fed mice, indicating that the absence of Ldlr does 
not affect the ASOs potency or lipid-lowering effects.  This suggests that administration of 
ANGPTL3 ASO administration is a promising target for clinical study in familial 
hypercholesterolemia patients. 
While formal pharmacology studies have not been conducted in the monkey with the human 
ANGPTL3 ASO, hepatic mRNA expression has been shown to be reduced by more than 60% in 
cynomolgus monkeys, the same model used to conduct the toxicology evaluation. 
2.3.3.2 
Preclinical Toxicology 
General toxicology studies for ISIS 703802 consisted of sub-chronic (16-week) and chronic (26- 
or 39-week) toxicity studies CD-1 in mice and cynomolgus monkeys.  Since ISIS 703802 is not 
fully complementary to the mouse ANGPTL3 transcript, treatment group receiving a mouse-
specific inhibitor (ISIS 731875) was also included in the mouse study.  Please refer to the 
Investigator Brochure for a detailed description of the preclinical toxicology and 
pharmacokinetics with ISIS 703802. 
Pharmacokinetic data confirmed continuous and dose-dependent exposure to ISIS 703802.  An 
estimated liver and plasma terminal elimination half-life values of approximately 1 week and 3-4 
weeks for 2 mg/kg and 35 mg/kg, respectively, were observed in monkeys.  The most 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
28 
noteworthy findings observed in mice and monkeys following ISIS 703802 treatment were, in 
general, non-specific class effects related to the uptake and accumulation of ASO and no 
toxicologically relevant findings were considered related to the pharmacologic inhibition of 
hepatic ANGPTL3 expression, either with the present series of studies or with the former 
development candidate targeting ANGPTL3.  There were no test-article related changes in PLT 
count in either mouse or monkey in both sub-chronic and chronic studies. 
The most noteworthy finding in the monkey was the kidney alteration (hypoalbuminemia and 
proteinuria) seen in one early-sacrifice animal from the 16-week study at 35 mg/kg/week, a dose 
equivalent to at least ~190-fold of the 40 mg weekly clinical doses by plasma AUC.  Non-dose 
dependent increases in renal protein excretion (up to 2.2-fold in quantitative urine protein, 
protein/creatinine ratio or urine albumin) were also observed at 8 and/or 35 mg/kg/week 
(> ~30 to 190-fold of the 40 mg weekly clinical doses by plasma AUC) at the 16-week scheduled 
terminal necropsy.  However, Similar kidney alterations were not seen at the 6-week interim at 
any doses or in the 39-week chronic monkey study up to 12 mg/kg/week (> ~200-fold of the 
20 mg weekly clinical dose by plasma AUC). 
Additional findings related to ASO liver accumulation included increased alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) at 
≥ 8 mg/kg/week in the 16- and 26-week mouse studies, and were correlated with individual 
hepatocyte necrosis (minimal to mild) in mouse liver.  Those changes were most prominent in 
the high dose groups (50 and 24 mg/kg/week for the 16- and 26-week studies, respectively).  
Conversely, no changes in liver enzymes were observed in monkeys from the 39-week toxicity 
study up to 12 mg/kg/week.  In the 16-week monkeys study, increase in ALT was only evident in 
one early-sacrifice animal at 35 mg/kg/week, and non-statistically significant increases in ALT 
(< 2-fold of the prestudy baseline) were also observed in the interim- and terminal-sacrifice 
animals at ≥ 8 mg/kg/week but showed no microscopic correlates or dose-dependency. 
Given the spectrum and severity of the test article-related clinicopathologic alterations present in 
monkeys at doses ≤ 12mg/kg/week (> ~100-fold of the 40 mg weekly clinical dose by plasma 
AUC) during the 39-week treatment phase, none would be regarded to represent an adverse 
effect (Dorato and Engelhardt 2005; Everds et al. 2013).  Considering the monkey to be the most 
relevant species, these data have characterized the safety profile and established appropriate 
therapeutic margins for the clinical evaluation of ISIS 703802 in humans. 
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 703802 can be found in 
the Investigator’s Brochure.  A summary is included below. 
The study drug, ISIS 703802, is being evaluated in Phase 1 in the clinical setting with single 
doses up to 120 mg and multiple doses up to 60 mg (once per week for 6 weeks).  The parent 
drug ISIS 563580, an unconjugated 2′-MOE modified ASO that has the same base sequence as 
ISIS 703802, was also evaluated in a blinded, placebo-controlled Phase 1 study. 
An interim analysis of ISIS 703802 Phase 1 SAD/MAD Study (ISIS 703802-CS1) was 
performed in 44 subjects administered single ascending (20, 40 and 80 mg) or multiple 
ascending doses (10, 20, 40 and 60 mg/week for 6 weeks).  Twelve participants were randomly 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
29 
assigned to single-dose groups (9 to active-agent dose groups and 3 to the placebo group) and 32 
were randomly assigned to multiple-dose groups (24 to active-agent dose groups and 8 to the 
placebo group).  The main endpoints of the study were safety, tolerability, pharmacokinetics, 
pharmacodynamics and changes in lipids and lipoproteins.  After 6 weeks of treatment, persons 
in the multiple dose groups treated with ISIS 703802 had dose-dependent reductions in levels of 
ANGPTL3 protein (reductions of 46.6 to 84.5% from Baseline, P < 0.01 for all doses vs. placebo 
1.6%) and in levels of triglycerides (reductions of 33.2 to 63.1% vs placebo 11.4%), LDL 
cholesterol (1.3 to 32.9% vs placebo 13.6%), very-low-density lipoprotein cholesterol (27.9 to 
60.0% vs placebo 4.0%), non–high-density lipoprotein cholesterol (10.0 to 36.6% vs placebo 
9.1%), apolipoprotein B (3.4 to 25.7% vs placebo 11.0%), and apolipoprotein C-III (18.9 to 
58.8% vs placebo 3.1%).  There were no serious adverse events documented during the trial.  No 
protocol-defined injection-site reactions were reported.  Of those participants who received the 
multiple-dose regimen, three reported headache (one who received placebo and two who 
received ISIS 703802) and three reported dizziness (two who received placebo and one who 
received ISIS 703802).  There was no clinical evidence of prothrombotic effects, bleeding 
episodes, significant decreases in platelet count or thrombocytopenia, or significant changes in 
renal function.  One subject in the 60 mg weekly dose cohort had an approximately 5 x ULN 
increase of ALT, without increase in bilirubin and a second subject had an ALT of 88 U/L on 
Day 36 post treatment which returned to normal range by Day 50 and remained normal until the 
end of the study.  One subject in the 20 mg MAD group was lost to follow-up after 5 doses.  
There were no other discontinuations during the treatment period (Graham et al. 2017 and data 
on file).  
The pharmacokinetics of ISIS 703802 evaluated in Study ISIS 703802-CS1 showed rapid 
absorption following SC administration, with median time to maximum plasma concentrations 
(Tmax) ranging from 1 to 6 hours.  Similar Tmax values were observed at all dose levels.  After 
reaching Cmax, plasma concentrations of ISIS 703802 declined in a multi-phasic fashion with a 
rapid disposition phase, followed by a slower elimination phase with terminal elimination half-
life of 3 to 5 weeks.  The peak (Cmax) and total exposure (AUC) after a single SC dose increased 
approximately dose proportionally from 20 to 40 mg, and greater than dose proportionally from 
40 to 80 mg, suggesting more efficient tissue uptake at lower doses.  After single and multiple 
SC doses in the range of 10 to 60 mg, the Cmax and AUC increased approximately dose 
proportionally.  No accumulation based on Cmax or AUC was observed after 6 weekly doses. 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD  
In a Phase 1 study, ISIS 563580-CS1, healthy volunteers received subcutaneous administration 
of ISIS 563580, an unconjugated 2′-MOE modified ASO that has the same base sequence as ISIS 
703802, from 50 to 400 mg as a single dose, or 100 to 400 mg as multiple doses (8 doses in 36 
days).  Overall, the safety findings from this study suggest that ISIS 563580 was not associated 
with any safety concerns.  There were 383 adverse events (AE) reported in the ISIS 563580-
treated subjects of which 363 (95%) were mild in severity.  For the multiple-dose subjects, the 
most common treatment-emergent adverse events were AEs at the injection site.  There was 1 
serious adverse event (SAE) in the study of periorbital cellulitis which was considered a 
medically important event by the Investigator and was also considered unlikely related to Study 
Drug by the Investigator.  Together, the above suggest that ISIS 563580 was well-tolerated at the 
doses and regimen given, which exceed the dose levels and cumulative exposures to be tested in 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
30 
the current study.  There were no clinically-relevant changes in laboratory assessments and the 
heparin dose of 80 U/kg was well-tolerated in support of the post-heparin procedures.  ISIS 
563580 produced dose-dependent reductions in plasma ANGPTL3 (up to 93%; group means up 
to 84%), TG (up to 63%; group means up to 49%) and TC (up to 46%; group means up to 28%) 
at Day 36 (Brandt et al. 2015). 
2.4 
Rationale for Dose and Schedule of Administration 
The Phase 1 program evaluated ISIS 703802 doses of 10 mg, 20 mg, 40 mg and 60 mg given 
weekly for 6 weeks that were found to be generally well-tolerated and to induce clinically-
relevant reductions in lipid biomarkers.  The dose proposed for the present study will provide the 
equivalent drug exposure of 20 mg weekly (80 mg monthly) and is predicted (based on 
modelling of PK/PD data obtained in Phase 1 study) to result in mean reductions from Baseline 
in TGs of approximately 63% at steady-state. 
Safety data from the available chronic mouse (26-week) and monkey (39-week) studies support 
once-weekly dosing for chronic administration.  The No Adverse Effect Level (NOAEL) for 
ISIS 703802 in chronic monkey study was determined to be 12 mg/kg/wk.    
In healthy volunteers, 703802 achieved an equivalent reduction in ANGPTL3 plasma 
concentration to that of the unconjugated form, at approximately 1/10th of the unconjugated ASO 
(ISIS 563580) dose (Brandt et al. 2015).   
2.5 
Benefit-Risk Assessment 
The current study is designed to evaluate the safety and tolerance of ISIS 703802 in patients with 
FPL.  The dose selected is expected to substantially reduce ANGPTL3 and result in a reduction 
of triglyceride levels, reduction of fat content of the liver and improvement of glycemic control.  
We do not know if subjects participating in this study would necessarily benefit from the 
treatment.  However, the increased understanding of the effects of ISIS 703802 in this population 
may potentially result in new treatment options that would ultimately benefit FPL patients.  Due 
to the short duration of this trial any benefit observed is not expected to persist beyond the end of 
the study.  
2.5.2 
Risk Assessment 
The known potential risks to study participants associated with ISIS 703802 are elaborated on in 
the Guidance to Investigator section of the Investigator’s Brochure.  
• In preclinical mouse studies, there were increases in ALT and AST and were correlated 
with increased incidence and/or severity of necrosis of individual hepatocytes (minimal 
to mild in severity).  Those changes were most prominent in the high dose groups and 
showed no clear progression over time.  No increases in liver enzymes were observed in 
monkeys from the 39-week toxicity study up to 12 mg/kg/week (~200-fold of the 20 
mg/week clinical dose by plasma AUC).  In the 16-week monkey study, increase in ALT 
was only evident in 1 early-sacrifice animal at 35 mg/kg/week, no meaningful increase in 
ALT was observed in the schedule sacrificed animals. 
• In the Phase 1 study, there was no elevations in ALT at single dose cohorts up to 120 mg.  
In multiple dose cohorts, two out of six subjects in the 60 mg weekly dose cohort had a    


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
31 
> 2 x ULN increase of ALT, without increase in bilirubin, which was considered a 
treatment related adverse event (AE) for one by Principal Investigator (PI).  There were 
no other observed clinically significant changes in ALT and liver function in Phase 1 
human study (data on file).  However, to evaluate and mitigate the potential for liver 
enzyme abnormalities, regular liver chemistry monitoring and stopping rules are included 
in the study as specified in Sections 8.5 and 8.6.  
• Injection site adverse events, while not considered safety issues, may affect the ability of 
the subject to tolerate dosing.  Injection site adverse events are the most common side 
effects observed following SC administration of unconjugated 2¢-MOE ASOs and are 
dose and concentration dependent.  Erythema is the most prevalent characteristic.  
Generally, these events are mild and reversible, resolve spontaneously and do not worsen 
with time.  The histologic findings are consistent with a local inflammatory response.  
Subjects should be informed of the possibility of occurrence of injection site adverse 
events.  Symptomatic interventions such as icing of the injection site or administration of 
NSAIDs prior to and/or after the SC dosing have been utilized. 
• Although no changes in platelet (PLT) counts have been observed in healthy volunteers, 
mouse or monkey in both sub-chronic and chronic studies with ISIS 703802, reductions in 
platelet counts to below the lower limit of normal have been observed after administration of 
other ASOs and some subjects have experienced severe thrombocytopenia following 
administration of unconjugated 2¢-MOE ASOs.  To evaluate and mitigate the potential for a 
reduction in PLT count, monitoring and stopping rules are included in the study as 
specified in Sections 8.5 and 8.6 (Safety Monitoring Rules and Stopping Rules). 
• No significant changes in serum creatinine, electrolytes, BUN, or urinalysis were 
reported from the interim analysis of the ongoing Phase 1 study (data on file).  To 
evaluate and mitigate the potential for a reduction in renal function, since kidneys are an 
organ of high distribution for the studied ASO, monitoring and stopping rules are 
included in the study as specified in Sections 8.5 and 8.6 (Safety Monitoring Rules and 
Stopping Rules). 
While the long term effects of reducing ANGPTL3 as a target with the study drug are not known 
at this time, there is evidence in literature in humans in whom ANGPTL3 is absent from plasma, 
due to homozygous or compound heterozygous ANGPTL3 mutations, present a pan-
hypobetalipoproteinemia phenotype, with generalized and marked decreases (~50% to 70%) in 
all apoB-100 containing lipoproteins, including VLDL and LDL, as well as HDL.  This clinical 
phenotype has been termed familial combined hypolipidemia or FHBL2 (Romeo et al. 2009; 
Musunuru et al. 2010; Martin-Campos et al. 2012; Minicocci et al. 2012; Noto et al. 2012; 
Pisciotta et al. 2012; Wang et al. 2015).  Clinical studies in FHBL2 suggest a trend toward lower 
glucose and insulin levels and reported decrease in VLDL.  Remarkably, diabetes and 
cardiovascular disease are reportedly absent from those with homozygous FHBL2 and no 
adverse clinical phenotype has been reported to date. 
2.5.3 
Overall Assessment of Benefit: Risk 
ISIS 703802 has demonstrated the ability to reduce ANGPTL3, APOCIII, and TGs by greater 
than 60% and LDL-C by more than 30% in the Phase 1 study in healthy volunteers.  The 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
32 
objective of this study is to assess the effect of TG lowering in FPL patients.  This study will also 
investigate the potential of ISIS 703802 in improving the insulin resistance and glucose profile, 
and decreasing liver and visceral fat content in these patients.  Although the subjects enrolled in 
this study will not derive long term benefits due to the short duration of the study, they may 
derive some short term benefit from improved metabolic health and dietary counselling.  The 
information obtained in the course of this study is critical to further development of ISIS 703802 
for FPL patients.  
The protocol identifies that potential risks associated with ISIS 703802 treatment will be 
mitigated by routine monitoring.  Thus, exposure of subjects in this study is justified by the 
anticipated benefits that may be afforded to the wider population of patients by continued 
development of ISIS 703802. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 2 open-label multiple-dose study of approximately 3 subjects with FPL that will 
be treated with ISIS 703802.  Initially, 3 subject will be enrolled, but enrollment could be 
increased to 6 subjects, based on safety profile and efficacy observations.  
Subjects will be evaluated for study eligibility during Screening and Qualification, which takes 
place up to 6 weeks prior to Day 1 (the first day of Study Drug administration).  During the 
Screening period, subjects will be advised to maintain routine diet and exercise routines, and 
remain on a stable regimen of diabetes and lipid medications (if they are already taking any).  As 
part of the Screening period, following 4 weeks of diet run-in, subjects will have a qualification 
visit and final eligibility assessments will be performed.  Subjects on stable diet known to the 
investigator and followed at the site may go from Screening to qualification without a 4-week 
diet run-in.  At the qualification visit TGs will be measured to qualify and MRI will be obtained 
to assess liver fat content.  MRI results must be available prior to registration and administration 
of the first dose of study drug. 
Subjects meeting eligibility criteria at qualification will return to the clinic on Day 1 for their 
first dose of ISIS 703802 by subcutaneous (SC) injection.  During the treatment period subjects 
will receive ISIS 703802 (20 mg) administered every week for 26 weeks. 
Subjects will return regularly for outpatient visits throughout the treatment period according to 
the Schedule of Procedures (Appendix A).  The primary safety and efficacy analysis time point is 
at Week 27.  
Subjects will then enter a 13 week Post-Treatment Follow-up Period and will return to the study 
center for outpatient evaluations according to the Schedule of Procedures (Appendix A). 
Blood and urine samples will be collected regularly throughout the study for safety, efficacy, and 
PK analysis.  Appendix B shows a list of analytes required for the study and Appendix C details 
the PK sample schedule. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
33 
3.2 
Number of Study Centers 
This study is planned to be conducted at a single center but will include additional centers if 
needed. 
3.3 
Number of Subjects 
Approximately 3 subjects will be treated in this study.  Initially, 3 subject will be enrolled, but 
enrollment could be increased to 6 subjects, based on safety profile and efficacy observations. 
3.4 
Overall Study Duration and Follow-up 
The length of subjects’ participation in the study may be up to 45 weeks.  This includes an up to 
5-week screening period, that includes a 4-week diet stabilization / run-in period, a 1-week 
qualification period, a 26-week treatment period, and a 13-week post-treatment evaluation 
period.  
Subjects may be required to attend additional visits for monitoring of adverse events or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Study 
Medical Monitor in consultation with the Investigator. 
3.4.1 
Screening/Qualification 
Subject eligibility for the study will be determined within 42 days/6 weeks prior to study entry.  
Potential subjects will report to the Study Center for screening assessments at specified intervals 
within the 6-week screening period as detailed in the Schedule of Procedures in Appendix A.  As 
part of the screening period, subjects will have a 4-week diet stabilization/run-in period followed 
by a up to 2-week qualification period.  Subjects on stable diet known to the investigator and 
followed at the site may go from Screening to qualification without a 4-week diet run-in.  At the 
qualification visit subjects will have a baseline DEXA scan and MRI will be obtained to assess 
liver fat content.  MRI results must be available prior to registration and administration of the 
first dose of study drug. 
3.4.2 
Treatment 
Eligible subjects will receive the first dose of study drug at the Study Center, at which time they 
will also be trained on self-administration of Study drug. Subsequent administrations of study 
drug may occur at home or in the Study Center.  
Eligible subjects will report to the Study Center for assessments at specified intervals throughout 
the 26 week treatment period as detailed in the Schedule of Procedures in Appendix A.  
3.4.3 
Post-Treatment 
Subjects are to return to the Study Center for follow-up visits.  These visits will take place at 4, 8 
and 13 weeks after the last dose. Refer to Schedule of Procedures in Appendix A. 
4. 
SUBJECT ENROLLMENT 
4.1 
Screening 
Before subjects may be enrolled into the Study, the Sponsor or designee requires a copy of the 
Study Center’s written independent ethics committee/institutional review board (IEC/IRB) 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
34 
approval of the protocol, informed consent form, and all other subject information and/or 
recruitment material.  
Subjects must sign the consent form before any screening tests or assessments are performed.  At 
the time of consent, the subject will be considered enrolled into the Study and will be assigned a 
unique subject identification number before any study procedures, including screening 
procedures, are performed.  This number will be used to identify the subject throughout the trial 
and must be used on all study documentation related to that subject.  The patient identification 
number must remain constant throughout the entire trial.  Subject identification numbers, once 
assigned, will not be reused. 
4.2 
Registration 
Subjects will be registered after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No subject 
may begin treatment prior to assignment of a unique subject identification number. 
4.3 
Replacement of Subjects 
Due to the small number of subjects participating in the study, subjects who withdraw from the 
study may be replaced by allowing a new subject to be screened and enrolled.  The subjects who 
withdrew for safety reasons will not be replaced.  
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 42 days of treatment 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 the time of informed consent   
3. Clinical diagnosis of familial partial lipodystrophy plus diagnosis of type 2 diabetes 
mellitus and hypertriglyceridemia.  
Diagnosis of lipodystrophy is based on deficiency of subcutaneous body fat in a partial 
fashion assessed by physical examination and low skinfold thickness in anterior thigh by 
caliper measurement: men (≤ 10 mm) and women (≤ 22 mm), and at least 1 of the 
following:  
- Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPAR-γ, AKT2, CIDEC, 
PLIN1 genes)  
OR 
- Family history of FPL or family history of abnormal and similar fat distribution plus 1 
Minor Criteria  
OR 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
35 
- 2 Minor Criteria (In the absence of FPL-associated genetic variant or family history) and 
BMI< 35 kg/m2  
 
MINOR Criteria  
f. Requirement for high doses of insulin, e.g., requiring ≥ 200 U/day, ≥ 2 U/kg/day, or 
currently taking U-500 insulin  
g. Presence of acanthosis nigricans on physical examination  
h. Evidence/history of polycystic ovary syndrome (PCOS) or PCOS-like symptoms 
(hirsutism, oligomenorrhea, and/or polycystic ovaries)  
i. History of pancreatitis associated with hypertriglyceridemia  
j. Evidence of non-alcoholic fatty liver disease  
- Hepatomegaly and/or elevated transaminases in the absence of a known cause of 
liver disease or radiographic evidence of hepatic steatosis (e.g., on ultrasound or 
CT)  
4. A diagnosis of diabetes mellitus, made at least 6 months prior to the Screening, and:  
• A HbA1c ≥ 7% to ≤ 12% at Screening,  
• On anti-diabetic therapy consisting of:  
d. Metformin ≥ 1500 mg/day, or  
e. If the dose of metformin is < 1500 mg/day, or metformin is not tolerated, then the 
patient should be on other oral anti-diabetic drugs (OAD) or an injectable 
glucagon-like peptide-1 (GLP-1) receptor agonist, or  
f. Insulin therapy alone or in combination with other anti-diabetic drugs 
5. Hypertriglyceridemia as defined by Fasting TG levels ≥ 500 mg/dL (≥ 5.7 mmol/L) at both 
Screening and Qualification visits. Patients with the clinical diagnosis of FPL and with 
Fasting TG levels ≥ 200 (≥ 2.26 mmol/L) to < 500 mg/dL (≥ 5.7 mmol/L) at both Screening 
and Qualification Visits who meet the genetic or family history criteria for study inclusion 
may be further screened and enrolled in the study 
 
6. Presence of hepatosteatosis (fatty liver), as evidenced by a Screening MRI indicating a 
hepatic fat fraction (HFF) ≥ 6.4% 
 
7. Willing to maintain their customary physical activity level and to follow a diet moderate in 
carbohydrates and fats with a focus on complex carbohydrates and replacing saturated for 
unsaturated fats 
 
8. 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 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
36 
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 at least 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 at least 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. A diagnosis of generalized lipodystrophy 
2. A diagnosis of acquired partial lipodystrophy (APL) 
3. Acute pancreatitis within 4 weeks of 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 heart failure requiring a change in medication 
5. Major surgery within 3 months of Screening  
6. History of heart failure with New York Heart Association functional classification (NYHA) 
greater than Class II or unstable congestive cardiac failure requiring a change in medication 
7. Uncontrolled hypertension (blood pressure [BP] > 160 mm Hg systolic and/or 100 mm Hg 
diastolic) 
8. Clinically-significant abnormalities in screening laboratory values that would render a 
subject unsuitable for inclusion, including the following: 
a. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR above 
this threshold, eligibility may be confirmed by a quantitative total urine protein 
measurement of ˂ 1 g/24-hr 
b. Estimated GFR ˂ 60 mL/min (as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance 
c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x ULN 
d. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in 
which case total bilirubin must be ≤ 3 mg/dL 
e. Alkaline phosphatase (ALP) > 1.5 X ULN 
f. Platelet count ˂ LLN 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
37 
9. Uncontrolled hyper- or hypothyroidism.  Subjects on dose stable replacement therapy for at 
least 3 months prior to Screening will be allowed 
10. History within 6 months of Screening of drug or alcohol abuse 
11. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Screening 
12. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
13. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or 
chronic hepatitis B 
14. 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 
15. Treatment with another investigational drug, biological agent, or device within 1-month of 
Screening, or 5 half-lives of investigational agent, whichever is longer 
16. Unwilling to comply with lifestyle requirements (see Section 6.3) 
17. Use of any of the following: 
a. Metreleptin within the last 3 months prior to Screening 
b. Antidiabetic, lipid lowering, or atypical antipsychotic medication, unless on a stable 
dose for at least 3 months prior to Screening.  For lipid lowering medications (e.g., 
omega-3 fatty acids) dose, brand and regimen are expected to remain the same from 
Day 1 throughout Week 13.  Patients not receiving these drugs within 4 weeks prior to 
Screening are also eligible 
c. Insulin unless on a stable daily basal insulin dose regimen (± 20 %) for at least 4 weeks 
prior to dosing 
d. GLP-1 agonists within 4 weeks prior to dosing, if patient has a history of pancreatitis 
e. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to Screening 
f. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Screening unless 
approved by the Sponsor Medical Monitor 
g. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to dosing 
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 throughout the study 
i. Oral anticoagulants unless on a stable dose for at least 4 weeks prior to dosing and 
regular clinical monitoring is performed 
j. Anti-obesity drugs [e.g., the combination of phentermine and extended-release 
topiramate (Qsymia), orlistat (Xenical), and lorcaserin (Belviq), phentermine, 
amphetamines, herbal preparations] within 12 weeks prior to Screening (except 
liraglutide [rDNA origin] injection (Saxenda) if on stable therapy for more than 6 
weeks prior to Screening). 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
38 
k. Any other medication unless stable at least 4 weeks prior to dosing (occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion) 
18. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 
60 days of Screening 
19. 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 
The study will consist of a Screening period, a Treatment period and a Post-treatment Follow-up 
period.  These periods are described below.  
All required study procedures are outlined in Appendix A. 
6.1.1 Screening/Qualification 
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures including screening procedures.  A 5-week period is provided for 
completing screening assessments and determining subject eligibility for the study.  During the 
screening period, subject will be advised to maintain diet and exercise routines, and remain on a 
stable regimen of diabetes and lipid medications (if they are already taking any).      
Subjects will undergo a medical history and physical examination including vital signs, 12-lead 
ECG, and have blood and urine samples taken for clinical laboratory testing.  Subjects will be 
screened for HIV, hepatitis B, and hepatitis C.  Safety labs may be re-tested for determination of 
subject eligibility after consultation with the Sponsor Medical Monitor. 
As part of the screening period, subjects not already on a stable diet will have 4 weeks of diet 
run-in, followed by a qualification visit, during which final eligibility assessments will be 
performed.  Subjects on stable diet known to the investigator and followed at the site may go 
from Screening to qualification without a 4-week diet run-in. At the qualification visit TGs will 
be measured and MRI will be obtained to assess liver fat content.  MRI results must be available 
prior to registration and administration of the first dose of study drug. 
6.1.2 Treatment Period 
Subjects will be managed on an outpatient basis.  Safety and clinical laboratory evaluations as 
well as blood sampling for PK analysis will be performed periodically throughout the treatment 
period.  Any AEs and concomitant medications will be recorded.  
Collection and measurement of vital signs, physical examination results, ECGs, clinical 
laboratory parameters (Appendix B), ISIS 703802 plasma concentrations, immunogenicity, MRI, 
AEs and concomitant medication/procedure information will be performed according to the 
Schedule of Procedures in Appendix A. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
39 
6.1.4 Post-Treatment Period 
Each subject will be followed for safety assessments for 13 weeks after the last dose of Study 
Drug.  During the post-treatment evaluation period, subjects will return to the Study Center for 
outpatient visits for safety and clinical laboratory evaluations.  A ± 3-day excursion from the 
scheduled visit date is permitted for this time period.  
6.2 
Study/Laboratory Assessments  
Laboratory analyte samples will be collected throughout the Study.  A list of these analytes is 
contained in Appendix B.   
Blood chemistry and urine samples (excluding 24-hour urine collection) should be taken after 
fasting for at least 10 hours.  During this time subjects can drink water and should ensure that 
they consume sufficient water to not become dehydrated.  
If tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or 
missing, a repeat blood or urine specimen should be re-drawn as soon as possible (ideally within 
1 week).  
While on treatment hematology samples will be collected every 14 days.  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 
samples are unreportable (e.g., due to hemolyzed or clumped blood samples), subject dosing 
cannot continue until another sample is repeated and determined not to have met a platelet 
stopping rule.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the subject to hold dosing until a new platelet count is obtained and reviewed.  
While on treatment blood samples for liver function testing will also be collected every 14 days 
and sent to the central laboratory for analysis for the first 3 months of the study treatment, and 
monthly thereafter during the Treatment Period per Section 8.5.1.   
While on treatment blood and urine samples for renal function testing will also be collected 
every 14 days and sent to the central laboratory for analysis per for the first 3 months of the 
study treatment, and monthly thereafter during the Treatment Period per Section 8.5.2.   
All lab samples sent to the central laboratory are received on the next day and processed.  Lab 
Alerts issued as per protocol safety monitoring requirements or stopping rules will indicate the 
applicable protocol section to facilitate review and will be immediately and simultaneously sent 
by email to the Investigator, the Sponsor and the CRO Medical Monitors, the Sponsor Drug 
Safety Physician, and the Clinical Trial Manager (CTM), and should be received by them within 
2 days from sample collection.  Hematology results from the site’s local laboratories are received 
by the study center staff on the day of sample collection, and should be entered as soon as 
possible into the eCRF to inform the Sponsor and CRO study monitoring teams.  
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the 
Investigator, or designee, to ensure that the count has not met the stopping rule and to determine 
whether the rate of decline is suggestive that the subject could be approaching the dose 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
40 
interruption rule of 75,000/mm3 as specified in Section 8.6.3.  Any case of a platelet count 
reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is considered an adverse event of 
special interest and must be reported in an expedited fashion to the Sponsor as per Section 9.4.1.  
All liver and renal function tests must also be reviewed promptly (within 48 hours of receipt) by 
the Investigator, or designee, to ensure that the result has not met the stopping rule.  Any event 
meeting renal stopping rules criteria described in Section 8.6.2 is considered an adverse event of 
special interest and must be reported in an expedited fashion to the Sponsor as per Section 9.4.1. 
All lab alerts received, including those related to platelet, liver, or renal function 
monitoring/stopping rules, are also reviewed promptly by the Sponsor and the CRO Medical 
Monitors who will agree on actions to be taken.  Within 24 hours of receiving an actionable lab 
alert the CRO Medical Monitor will communicate instructions to the Investigator and the study 
personnel by emailing them the Safety Surveillance Form that needs to be signed by the 
Investigator/study personnel and promptly returned to the Sponsor and CRO Medical Monitor.  
In urgent cases, such as platelets results below 50,000/mm3, or liver or renal test results reaching 
a critical stopping rule the Investigator must also be contacted by phone.  
Further information on safety monitoring and actions to be taken by the Study Investigator in the 
event of reduced platelet count are provided in Sections 8.5.3 and 8.6.3. 
6.2.1 
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 (BP), pulse rate, respiratory 
rate and body temperature.  BP and pulse rate will be recorded after the subject has been in a 
sitting position for at least 5 minutes.  BP should always be measured on the same arm 
(preferentially on the left arm).  Height will be measured at Screening. 
6.2.2 
DEXA Scan 
Dual-energy X-ray Absorptiometry (DEXA) scans will be conducted prior to administration of 
the first dose of Study Drug and repeated at Week 27 using standardized procedures and settings. 
6.2.3 
Electrocardiography  
Electrocardiography (ECG) will be conducted as indicated in the Schedule of Procedures 
(Appendix A) at Screening, Day 1 (prior to the first dose of Study Drug), and during the 
treatment period.  
ECGs will be conducted during the post-treatment follow-up period at scheduled visits. 
ECGs will be recorded after the subject has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate. 
6.2.4 
PK Sampling 
Blood samples for the determination of plasma ISIS 703802 concentrations will be collected 
prior to dosing on Day 1 and at various times throughout the treatment and post-treatment 
follow-up periods as noted in the tables in Appendix C. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
41 
6.2.5 
Mixed Meal Test 
The Mixed Meal Test (MMT) (Appendix E) will be done at baseline, at week 13 and at week 27.  
This test consists of having the subject consume a standardized meal in the evening and fast 
overnight for at least 8 hours.  The following morning, before the test, fasting plasma glucose, 
free fatty acids (FFA), C-peptide, insulin, serum ghrelin, GIP, GLP-1 and PYY as well as 
incretin hormones are measured.  The subject then consumes a liquid standard meal (such as 
Optifast®) and the same metabolic parameters are measured again over the course of 300 minutes 
at 10, 20, 30, 60, 90, 120, 150, 180, 240 and 300 minutes. In addition, a validated visual 
analogue scale (VAS) will be used to measure the subject’s perception of hunger. 
6.2.6 
MRI 
An MRI to determine liver fat fraction will be done at Qualification, Week 13 and Week 27.  
6.3 
Restriction on the Lifestyle of Subjects 
6.3.1 
Contraception Requirements 
All male subjects and women of childbearing potential must refrain from sperm/egg donation 
and either be abstinent† or practice effective contraception from the time of signing the informed 
consent form until at least a period of 13 weeks after their last dose of study treatment.  
Male subjects engaged in sexual relations with a female of child-bearing potential must also 
encourage their female partner to use effective contraception from the time of signing the 
informed consent until a period of 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 subjects: 
• 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 subjects with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug 
For female subjects and female partners of male subjects: 
• Using 2 of the following acceptable methods of contraception:  surgical sterilization (e.g., 
bilateral tubal ligation), hormonal contraception, intrauterine contraception/device, or any 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
42 
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: 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. 
*Note: A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
6.3.2 
Other Requirements 
All subjects will be required to fast for at least 10 hours before visits requiring fasted blood 
sampling.   
7. 
STUDY DRUG 
7.1 
ISIS 703802  
Study Drug (ISIS 703802) characteristics are listed in Table 1. 
Study Drug (ISIS 703802) will be provided as 0.8 mL deliverable volume in 2 mL stoppered and 
sealed glass vials as a sterile solution.   
The Study Drug is clear to slightly yellow in color, it is for single use, contains no preservatives 
and must be stored between 2 to 8 °Celsius and be protected from light. 
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 703802 
Strength 
100 mg/ mL  
Volume/Formulation 
0.8 mL/vial 
Route of 
Administration 
SC* 
* 
SC = subcutaneous 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with 
specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug (ISIS 
703802) supplies provided by the Sponsor.  The subject must return all used and unused Study 
Drug to the Study Center for accountability. The Study Center must return all used and unused 
Study Drug to the Sponsor or designee.  All used syringes must be disposed of as per the site’s 
hazardous waste destruction policy. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
43 
8. 
TREATMENT OF SUBJECTS 
8.1 
Study Drug Administration 
Vials are for single use only.  Study staff will administer the first dose of Study Drug.  Doses 
will be administered by SC injection, patients or their caregivers may self-administer the study 
drug following the training given by the study center staff.   
Subjects will receive treatment weekly with weeks always defined relative to Study Day 1.  For 
example if a subject receives the first dose on a Monday, subsequent doses should be given on 
Mondays according to the respective dosing schedule, if possible.  If a subject misses an 
injection, or if dosing on the usual day is not possible, the subject can reschedule the injection 
provided that 2 doses are administered at least 2 days apart.   
Every effort should be made to ensure the previous dose is given 7 days prior to a scheduled 
clinic visit. 
Volumes to be administered are shown in Table 2.  Please refer to the Study Drug Manual 
provided by the Sponsor or designee for more detailed instructions for Study Drug preparation 
and/or administration.  
Table 2 
Study Drug Dosing Information 
Volume to Administer* 
Total Dose* 
0.20 mL  
20 mg (open label) 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs.  
Subjects will continue their lipid-lowering therapy on a stable regimen from the signing of 
informed consent at Screening through the end of the post-treatment evaluation period. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures other than those outlined in the 
schedule of procedures. 
8.4 
Treatment Precautions 
No specific treatment precautions are required. 
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 the pre-dose test 
closest to Day 1 and Day 1. 
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.  


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
44 
In case of discrepancy between the test results from 2 sources, safety-mandated action must be 
initiated based on the more critical (lower or higher, as relevant) of the 2 values.  
Confirmation Guidance:  At any time during the Study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 
initial measurement) on new specimens prior to administering the next dose of Study Drug.  All 
new specimen collections should take place as soon as possible (ideally within 3 days of the 
initial collection).   
Stopping Rule Guidance:  The Investigator may interrupt or permanently discontinue study 
treatment for any safety reason including clinically meaningful changes in clinical laboratory 
results.  
In the event of an initial clinical laboratory result that meets a stopping criterion, subjects must 
not be re-dosed until a confirmatory test result has been reviewed by the Study Medical Monitor.  
If any of the stopping criteria described below are met and are confirmed, the subject will be 
permanently discontinued from further treatment with Study Drug (ISIS 703802), evaluated fully 
as outlined below and in consultation with the Study Medical Monitor or appropriately qualified 
designee, and will be entered into the post-treatment evaluation portion of the study.  In general, 
subjects who do not meet the stopping rules based upon retest may continue dosing.  However, 
the Investigator and the Study Medical Monitor (or appropriately qualified designee) should 
confer as to whether additional close monitoring of the subject is appropriate.  
Additional Guidance:  If possible, a PK sample should be collected as soon as possible after a 
SAE has occurred (preferably within 2 weeks).  In addition, if a subject is asked to return to the 
clinic for additional evaluations due to an AE, then a PK sample should be taken at the time of 
the unscheduled visit. 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the FDA 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 and adopted to meet the requirements of this 
protocol and compound to ensure safety of the subjects.   
While on treatment, all subjects will have liver chemistry tests monitored every 2 weeks during 
the first 3-months of the study treatment period, and monthly thereafter.  Upon completion of the 
study treatment period, liver chemistry tests should be monitored as per visit schedule in 
Appendix A.  
In the event of appearance of symptoms or signs of hepatic injury (jaundice, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, abnormal bleeding or bruising, or 
eosinophilia  > ULN) liver enzymes and bilirubin should be tested as soon as possible.  Testing 
at a lab that is local to the subject is permissible for this purpose. 
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. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
45 
Subjects with confirmed ALT or AST levels > 3 x ULN should have their liver chemistry tests 
(ALT, AST, ALP, international normalized ratio [INR] and total bilirubin) retested at least 
once-weekly until ALT and AST levels become ≤ 1.5 x ULN. 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules. 
Further Investigation into Liver Chemistry Elevations:  For subjects with confirmed ALT or AST 
levels > 3 x 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 (hepatitis A virus [HAV] immunoglobulin M [IgM], hepatitis 
B surface antigen [HBsAg], hepatitis C virus [HCV] antibody, Cytomegalovirus [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 
subject’s ALT and/or AST levels reach 5 x ULN. 
All routine liver function test results will be reviewed on an ongoing basis by the Medical 
Monitor.  
All lab alerts for abnormal liver function tests must be promptly (within 48 hours of receipt) 
reviewed by the Investigator and Medical Monitors. 
Lab alerts for abnormal liver chemistry tests will be issued for:  1) ALT or AST > 3 x ULN; 
2) ALT or AST > 2 x baseline; 3) total bilirubin > ULN; 4) ALP > ULN.  These alert levels are 
set to anticipate the risk of a combined elevation of aminotransferases and bilirubin as per the 
FDA Guidance. 
8.5.2 
Safety Monitoring for Renal Function 
While on treatment all subjects will have renal function tests monitored every 2 weeks during the 
first 3 months of the study treatment period, and monthly thereafter.  Upon completion of the 
study treatment period, urine renal biomarkers should be monitored as per visit schedule in 
Appendix A.  
In the event of appearance of symptoms or signs consistent with renal dysfunction such as 
hematuria, polyuria, anuria, flank pain, new-onset hypertension, nausea and/or anorexia, renal 
function should be tested as soon as possible.  Testing at a lab that is local to the subject is 
permissible for this purpose. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
46 
While on treatment during the course of the study, urinary surveillance may include urinalysis to 
include urine albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and 
urinary red blood cells (RBCs), as well as serum creatinine and cystatin-C to estimate glomerular 
filtration rate (eGFR) which will be monitored every 2 weeks during the first 3-months of the 
study treatment period, and monthly thereafter.  In addition, other biomarkers of acute renal 
injury may also be measured if a safety signal is seen that warrants further testing.  (Appendix 
B).  
The assessment of serum creatinine, cystatin-C, and urinalysis more frequently than per the 
Schedule of Procedures in Appendix A will be guided by consultation with the medical monitor.  
Any decision taken by the Investigator to discontinue study medication will be made taking into 
account all available and relevant data.  In addition, the decision to discontinue Study Drug may 
also be based on lesser changes in these parameters observed in isolation or in association with 
other renal-related abnormalities.  Any decision taken to restart study medication will be made in 
consultation with the Study Medical Monitor taking into account all available and relevant data.  
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules. 
Lab alerts for abnormal renal tests will be issued for:  Creatinine clearance (by CKD-EPI 
formula) decrease from Baseline > 25%, urine albumin/creatinine ratio (UACR) > 250 mg/g, 
urine protein/creatinine ratio (UPCR) > 0.5 mg/mg, or an increase in serum creatinine from 
Baseline > 0.3 mg/dL). 
These alert levels are set to anticipate and prevent the risk of a medically significant change in 
renal function while receiving Study Drug. 
In the event of a confirmed laboratory result meeting one or more of the above criteria, the 
following supplemental renal tests should be immediately obtained:  
Serum creatinine, urine culture, 24-hour urine sample for creatinine clearance, urine 
albumin and urine protein, urine microscopy sample with inspection of sediment. 
The Investigator should also review the subject’s concomitant medications for potentially 
nephrotoxic agents, and, with the results of these evaluations, review any decision to continue or 
discontinue the subject in consultation with the Study Medical Monitor. 
8.5.3 
Safety Monitoring Rules for Platelet Count Results 
All subjects will have platelet counts monitored every 2 weeks for the duration of the study 
treatment period and must not receive Study Drug without an interpretable platelet count result in 
the prior 2 weeks.  Upon completion of study drug dosing, platelets should be monitored every 2 
weeks for the first 6 weeks and then at 8 and 13 weeks post last dose (as per visit schedule).  
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the count has not met the stopping rule and to 
determine whether the rate of decline is suggestive that the subject could be approaching the 
dose interruption rule of 75,000/mm3.   


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
47 
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is 
considered an adverse event of special interest and should be reported in an expedited fashion to 
the Sponsor.  
Lab alerts related to platelet monitoring/stopping rules are issued when:  1) platelet counts are 
< 140,000 mm3; 2) when platelet count is ≥ 30% decreased from Baseline, or 3) when the 
hematology sample is unreportable.  All these lab alerts, are reviewed promptly by the Medical 
Monitor and instructions are communicated to the Investigator and the study personnel within 
24 hours of receiving an actionable lab alert. 
Actions to be taken in the event of reduced platelet count are shown in Table 3. 
In the event of a platelet count ˂ 100,000/mm3 the laboratory tests outlined in Table 3, should be 
performed as soon as possible.  Additional lab tests will be determined by the Sponsor Medical 
Monitor or designee in consultation with the Investigator.  
8.5.4 
Safety Monitoring for Bleeding Events 
Subjects will be evaluated for occurrence of bleeding events continuously after the start of Study 
Drug treatment (Day 1).  Patients will be instructed to promptly report any signs or symptoms of 
bleeding.  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, or 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, hepatic enzymes, bilirubin and platelet count may be performed. 
8.5.5 
Safety Monitoring for Constitutional Symptoms 
Subjects will be instructed to promptly report any signs or symptoms of fever, constitutional 
symptoms, rash, arthralgia or joint swelling that may arise during the study and the Investigator 
should closely evaluate all potential causes, including concomitant illness.  Subjects who 
experience persistent symptoms should be discussed with the Sponsor Medical Monitor or 
designee to determine whether additional monitoring or laboratory tests are required.   
8.5.6 
Safety Monitoring for Hypoglycemia 
Subjects will be instructed to monitor and manage hypoglycemic episodes. Subjects will be 
provided with glucometer and asked to record Self Monitored Blood Glucose (SMBG) levels and 
report back alert values to the site.  Subjects will be instructed to promptly report symptoms of 
hypoglycemia: headache, heart pounding, confusion, disorientation, numbness or tingling, pale 
skin, shakiness or tremulousness, increased appetite, anxiousness or nervousness, 
lightheadedness or dizziness, sweating and weakness.  If subjects 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.  If a subject presents with symptoms of hypoglycemia, the Investigator will need to 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
48 
take immediate action to confirm the subject’s glucose level and treat the subject accordingly.  
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
Classification of Hypoglycemia 
The alert value for hypoglycemia is ≤ 70 mg/dL (≤ 3.9 mmol/L) plasma concentration. 
Severe Hypoglycemia 
Requires assistance of another person to actively administer carbohydrates, glucagon, or take 
other corrective actions.  Plasma glucose concentrations may not be available during an event.  
Neurological recovery following plasma glucose levels returning to normal considered sufficient 
evidence that event was induced by low plasma glucose concentration. 
Documented Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms accompanied by measured plasma glucose ≤ 70 mg/dL (≤ 3.9 
mmol/L).  
Asymptomatic Hypoglycemia  
Not accompanied by typical hypoglycemia symptoms but with measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L). 
Probable Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms not accompanied by plasma glucose determination but likely 
caused by plasma glucose ≤ 70 mg/dL (≤ 3.9 mmol/L). 
A documented severe hypoglycemic event is defined as one in which the subject 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 
subjects at risk for injury to themselves or others. 
8.5.7 
Safety Monitoring for Documented Hyperglycemia 
Subjects will be asked to self-monitor their glucose at least once a week and reviewed by 
Investigator at each Study Center visit.  If the value exceeds the specific glycemic limit specified 
below, the subject will be instructed to check again during the 2 following days.  If all values in 
3 consecutive days exceed the specific limit, the subject should contact the Investigator and a 
central laboratory FPG measurement will be performed).  
The threshold values are defined as follows, depending on study period: 
From baseline visit to Week 13 (including value at Week 13) of Randomized Treatment period: 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
49 
• FPG > 270 mg/dL (15.0 mmol/L) 
From Week 13 to Week 25/27/ET (including value at Week 25/27/ET) of Randomized 
Treatment period: 
• FPG > 240 mg/dL (13.3 mmol/L) or 
• HbA1c > 9% (for subjects with Baseline HbA1c < 8%) and HbA1c increase of more than 
1% from Baseline (for subjects with Baseline HbA1c ≥ 8%) 
In case of FPG/HbA1c above the threshold values, 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 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency such as unplanned hospitalization (e.g., surgery, infection), the Investigator 
can take appropriate measures for glycemic control.  If the measure does not exceed 7 
days, then it will not be considered a rescue.  If the measure lasts beyond 7 days then it 
will be treated as a rescue 
• 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 undertake appropriate action, i.e.: 
• Investigation and treatment of intercurrent disease (to be reported in AE/concomitant 
medication parts of the eCRF) 
• 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 
• Schedule a FPG/HbA1c assessment at the next visit 
If none from the above-mentioned reason can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, rescue medication may be introduced at the Investigator 
discretion and according to local guidelines. 
All assessments for primary and secondary efficacy and safety parameters planned in final 
primary endpoint assessment visit should be performed before adding the rescue medication if 
possible.  Then the subject continues the study treatment and stays in the study in order to collect 
safety information.  The planned visits and assessments should occur until the last scheduled 
visit.  (See more details in Appendix A). 
Note: After Study Drug discontinuation any treatments are permitted, as deemed necessary by 
the Investigator. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
50 
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 confirmed laboratory results meeting any of the following criteria, dosing of a 
patient with Study Drug will be stopped permanently: 
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. 
Dose adjustments, including dose interruptions, and/or decreasing the dose or dose frequency 
will be allowed for safety.  Any proposed adjustments to treatment schedule must be discussed 
with, and approved by, the Study Medical monitor prior to initiation.  
8.6.2 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for 
Renal Function Test Results 
In the event of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the 
following criteria, or any change in renal biomarkers deemed by the nephrologist to require 
further evaluation, a serum creatinine and 24-hour urine sample for creatinine clearance and 
protein should be obtained: 
1. CKD-EPI decrease of > 40% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (ISIS 703802) will be stopped permanently if 24-hour urine 
testing confirms any of the following values in the absence of an alternative explanation: 
1. Urine protein is > 1.0 g 
2. Creatinine clearance decrease of > 40% from Baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, the follow-up schedule and 
frequency of renal function monitoring after the initial event will be determined by the Study 
Medical Monitor in consultation with the Investigator.  The Investigator should consider 
consulting a local nephrologist for any change of renal function that presents a concern.  If a 
renal biopsy is performed, a sample specimen should be made available for examination by an 
independent renal pathologist who has been engaged by the Sponsor to review such specimens.  


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
51 
Dose adjustments, including dose interruptions, and/or decreasing the dose or dose frequency 
will be allowed for safety.  Any proposed adjustments to treatment schedule must be discussed 
with, and approved by, the Study Medical monitor prior to initiation.  
8.6.3 
Stopping Rule 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 any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 
that occurs while the subject is already on reduced dose, dosing of the subject with Study Drug 
will be stopped permanently (Table 3).  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 subjects 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 ˂ 75,000/mm3 and > 50,000/mm3, dosing of a subject with Study 
Drug should be suspended temporarily until the platelet count has recovered to > 100,000/mm3.  
If dosing is continued, it must be at a reduced dose as shown in Table 1.  The suitability of the 
subject 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 
subject’s platelet count, whether any bleeding events were experienced by the subject, and the 
speed of recovery of platelet count after interruption of dosing. 
If, after reintroduction of Study Drug, the platelet count again falls below 75,000/mm3, then 
dosing of the subject with Study Drug will be stopped permanently.  
Once a subject commences weekly monitoring, this frequency of monitoring should continue 
irrespective of whether the platelet count rises into the normal range. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue. 
Bleeding events that are either major or clinically-relevant non-major bleeding (as defined 
below) will need to be monitored and treated immediately. Subjects with a suspected bleeding 
event will undergo additional testing if deemed appropriate by the treating physician and an 
(S)AE case report form will be completed. In addition, if bleeding is considered significant, 
hemoglobin (Hb), hematocrit (HCT), aPTT, PT, INR, and platelet count are to be obtained.  In 
addition, approximately 2 mL of K2EDTA anticoagulated blood will be collected and resulting 
plasma must be stored allowing for a centralized assessment of ISIS 703802 concentrations.  
In addition, if a minor bleeding event occurs, the Investigator should notify the Sponsor Medical 
Monitor (or designee) and additional testing of coagulation parameters (aPTT, prothrombin time 
[PT], INR), platelet count, and platelet volume may be performed. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
52 
Definitions:  
Major bleeding (MB) is defined as one of the following (Büller et al. 2007):  
1. Fatal bleeding  
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or 
intramuscular with compartment syndrome  
3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed red blood cells or 
whole blood or a fall in hemoglobin of 20 g/L (1.24 mmol/L) or more within 24 hours  
Clinically-relevant non-major bleeding (CRNMB) is defined as overt bleeding not meeting the 
criteria for major bleeding but that resulted, for example, in medical examination, intervention, 
or had clinical consequences for a subject (Büller et al. 2007).  
 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (defined above), for example excess bruising, petechiae, 
gingival bleeding on brushing teeth. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
53 
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 week* 
75K-100K/mm3 
Permanently reduce as follows: 
Reduce to 10 mg every week 
Closer observation 
Monitor every week* 
50K-75K/mm3 
Pause dosing 
When platelet count returns to > 100K/mm3 restart 
dosing as follows only if approved by Sponsor 
Medical Monitor: 
Reduce to 10 mg every week 
or 
Permanently discontinue Study Drug if it occurs 
while on already reduced dose  
Closer observation 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/non-
steroidal anti-inflammatory 
drug (NSAIDS)/ anticoagulant 
medication 
25K-50K/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 
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 
* 
Once a patient commences weekly monitoring this frequency of monitoring should continue irrespective of 
whether the platelet count rises into the normal range. 
** 
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 and/or Treatment Schedule 
Dose frequency adjustments for platelet count reduction must be made in accordance with 
Section 8.6.3 and Table 3 (above). 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
54 
Other dose adjustments, including dose interruptions, and/or decreasing the dose will be allowed 
for safety or tolerability in consultation with the Sponsor Medical Monitor.   
Subjects may have their dose interrupted in response to AEs in consultation with Study Medical 
Monitor. 
8.8 
Discontinuation of Study Drug/Treatment 
A subject must permanently discontinue study treatment for any of the following: 
• The subject becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The subject withdraws consent 
• The subject experiences an adverse event (AE) that necessitates permanent 
discontinuation of Study Drug 
• The subject develops laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1 to 8.6.3 
• When a platelet count of less than 50,000/mm3, or a platelet count less than 75,000/mm3 
while the patient is on a reduced dose. 
The reason for discontinuation of Study Drug Treatment must be recorded in the electronic Case 
Report Form (eCRF) and source documentation.  
For subjects who discontinue treatment early every effort should be made to complete the early 
termination study procedures and observations at the time of withdrawal (see Appendix A).  
Subjects should then be entered into the post-treatment evaluation period.   
If a subject discontinues treatment after only 1 dose, then the post-treatment evaluation 
procedures should be followed.  
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period 
Any subject who discontinues early from the treatment period or from post-treatment follow-up 
period should be followed as per the platelet monitoring rules shown in Table 3, 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 13 weeks after discontinuing Study Drug.  If the subject 
declines or is unable to participate in the above, the early termination visit procedures should be 
performed at the time of withdrawal, at a minimum, and ideally within 2 weeks from the last 
dose of Study Drug.  In addition, the investigator should clarify what type of follow-up the 
subject is agreeable to: in person, by phone/mail, through family/friends, in 
correspondence/communication with other physicians, and/or from review of the medical 
records.  Wherever possible these subjects should continue to be followed up via the agreed 
means to collect information on adverse events, concomitant medications and survival status.  At 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
55 
the very least, the patient’s status at the end of the protocol defined study period should be 
ascertained and documented. 
8.9 
Withdrawal of Subjects from the Study 
Subjects must be withdrawn from the Study for any of the following: 
• Withdrawal of consent 
• The subject is unwilling or unable to comply with the protocol 
• The subject meets any of the Exclusion Criteria (see Section 5.2) after enrolling in the 
study that in the opinion of the Investigator represents a safety risk to the subject 
Other reasons for withdrawal of subjects 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 eCRF.  
Any subject who withdraws consent to participate in the Study will be removed from further 
treatment and study observation immediately upon the date of request.  These subjects should be 
encouraged to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix A). For subjects 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 Appendix A).  The Investigator should clarify what type of follow-
up the subject is agreeable to: in person, by phone/mail, through family/friends, in 
correspondence/communication with other physicians, and/or from review of the medical 
records.  Wherever possible these subjects should continue to be followed up via the agreed 
means to collect information on adverse events, concomitant medications and survival status.  At 
the very least, the patient’s status at the end of the protocol defined study period should be 
ascertained and documented. 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
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 Screening and the end of the post-treatment evaluation period. All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a subject, including changes in the subject’s current medications, must be 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
56 
recorded in the subject’s source documents and CRF.  Subjects 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 
Ibuprofen may be used for symptomatic pain relief.  Any other therapy (including OTC 
medications) should be approved by the Sponsor Medical Monitor or designee. Any medications 
deemed necessary by the Investigator are allowed except those listed in the disallowed 
concomitant therapy.  
Disallowed Concomitant Therapy 
The use of prescription and OTC medications including nonsteroidal anti-inflammatory drugs 
(with the exception of occasional ibuprofen) is prohibited during this study unless the occurrence 
of an AE requires a drug therapy.  In such cases, the Investigator must consult the Sponsor 
Medical Monitor to decide on subject continuation or withdrawal from the study.  
The medications and therapy identified in exclusion criteria, Section 5.2 are also disallowed 
concomitant medications and are prohibited during the course of study, unless there is a safety 
concern.  In those cases the Medical Monitor needs to be notified and rationale provided by the 
Investigator. 
Concomitant therapy with oral corticosteroids used as replacement therapy for pituitary adrenal 
disease as well as inhaled steroid therapy (e.g., Pulmicort®), or intra-articular, or topical may be 
acceptable; however, the subject must be on a stable regimen for at least 4 weeks prior to 
Screening.  All exceptions should be discussed with the Sponsor Medical Monitor. 
Subject 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 
Screening and the end of the post-treatment evaluation period. 
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 
study medication.  Subjects that are self-administering study medication 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 or designee in 
accordance with the Safety Management Plan throughout the conduct of the clinical trial. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
57 
9.2 
Regulatory Requirements 
The Sponsor or designee 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. 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. For the 
purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population. 
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 AE caused by the Study Drug. A suspected adverse reaction is any 
AE for which there is a reasonable possibility that the 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 subject 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 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
58 
• Results in a congenital anomaly or birth defect in the offspring of the subject (whether 
the subject 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 subject 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. 
9.3.3.1 
Adverse Events of Special Interest 
For the purpose of this study severe reductions in platelet count < 50,000 mm3 are considered as 
an AE of special interest and should be subject to expediting reporting to the Sponsor following 
the same requirements as for SAE reporting (Section 9.4.1). 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject 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 subject safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) 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 subject signs the informed consent form and stop at the end of the subject’s 
follow-up 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.   
The contact information for reporting SAEs is as follows: 
Attention:  
INC Research, LLC 
Email: 
 
INCDrugSafety@INCResearch.com 
Fax: 
 
1-877-464-7787 
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 subject’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
subject’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
59 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent form 
and will stop at the end of the subject’s follow-up period.  The Investigator will monitor each 
subject 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 the Study Drug (ISIS 703802) is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug, e.g., 
confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the subject’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and Study Drug (ISIS 703802) 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 
Study Drug (ISIS 703802) 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 subject’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and Study Drug 
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 subject and does not affect the subject’s usual 
daily activities 
• Moderate:  The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
subject’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). 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
60 
9.4.3.3 
Action Taken with Study Drug 
Action taken with Study Drug (ISIS 703802) due to the event is characterized by 1 of the 
following: 
 
• None:  No changes were made to Study Drug (ISIS 703802) administration and dose 
• Permanently Discontinued:  Study drug 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 
• Temporarily Interrupted, Restarted Reduced Dose:  Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the next lower dose 
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 eCRF, 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:  Subject terminates from the trial and the AE continues: 
 
• Recovered:  Subject 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 an SAE, then the event’s outcome is characterized by 1 of the following: 
Ongoing:  SAE continuing: 
 
• Persists (as non-serious AE):  Subject 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:  Subject recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Subject died (the date of death should be entered as the SAE resolution date) 
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, 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
61 
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. All platelet count results must 
be reviewed promptly (within 48 hours of receipt) by the Investigator or the designee 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 interruption rule of 75,000/mm3 as 
specified in Section 8.6.3. Any case of a platelet count reduction to levels below 50,000/mm3 
(Grade 3 or Grade 4) is considered an adverse event of special interest and should be reported in 
an expedited fashion to the Sponsor as per Sections 9.3.3.1 and 9.4.1). 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.1. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.2. 
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 subject 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 subject’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 subject’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 
Study Drug (ISIS 703802) errors should be documented as Protocol Deviations.  A brief 
description should be provided in the deviation, including whether the subject was symptomatic 
(list symptoms) or asymptomatic, and the event accidental or intentional. Dosing details should 
be captured on the Dosing eCRF.  If the subject takes a dose of Study Drug that exceeds protocol 
specifications and the subject is symptomatic, then the symptom(s) should be documented as an 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
62 
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 
Subjects must continue to use appropriate contraception with their partners, or refrain from 
sexual activity, as described in Section 6.3.1.  If a subject becomes pregnant or a pregnancy is 
suspected, or if a male subject 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 
by designating as ‘Follow-up’ on the Pregnancy Forms and reported within 24 hours.  Payment 
for all aspects of obstetrical care, child or related care will be the subject’s responsibility.  
Female subjects:  If a suspected pregnancy occurs while on the Study (including follow-up), a 
pregnancy test will be performed.  The subject with a confirmed pregnancy will be immediately 
withdrawn from treatment with Study Drug.  However, the subject 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 subject 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.  Follow-up will be performed to the extent permitted by the applicable regulations 
and privacy considerations.  Male subjects:  The progress of the pregnancy of a male subject’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 the 
applicable regulations and privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
10.1.1 
Primary Endpoint 
• The effect of ISIS 703802 on the percent change from Baseline in fasting triglyceride 
levels (TG) at week 27 
10.1.2 
Secondary Endpoints 
• Change from Baseline in AUC plasma glucose, serum insulin, serum C-peptide, free fatty 
acid, serum ghrelin, GIP, GLP-1, and PYY and incretin hormones in response to a mixed 
meal test (MMT) 
• Change from Baseline in lipids and lipoproteins including high-density lipoprotein 
cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol 
(TC), very low-density lipoprotein cholesterol (VLDL-C), non-HDL-C, apolipoprotein B 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
63 
(apoB), apolipoprotein B-48 (apoB-48), apolipoprotein B-100 (apoB-100), apolipoprotein 
A-1 (apoA-1), apolipoprotein C-III (apoC-III :total, chylomicron, VLDL, LDL and 
HDL), Lipoprotein a [Lp(a)], free fatty acids (FFA), and glycerol levels, lipoprotein 
particle size/number 
• Change from Baseline in glycosylated hemoglobin (HbA1c) 
• Change from Baseline in homeostasis model assessment-estimated insulin resistance 
(HOMA-IR) 
• Change from Baseline in adiponectin and leptin 
• Change from Baseline in hepatic fat fraction (as assessed by magnetic resonance imaging 
[MRI]) 
• Changes from Baseline in body fat distribution for various areas in the body as measured 
by skinfold thickness and DEXA; VAT and SAT as measured by MRI; body weight, 
waist circumference and waist/hip ratio 
• Change from Baseline in quality of life and pain score 
10.2 
Sample Size Considerations 
There is no statistical rationale for the selected sample size.  The sample size is selected based 
upon prior experience with ISIS 703802 to ensure that the safety, tolerability and efficacy of ISIS 
703802 can be explored in an ultra-rare condition before enrolling subjects in a larger study.   
10.3 
Populations 
Safety Set:  All subjects who are enrolled and receive at least 1 dose of Study Drug.  PK Set:  All 
subjects who receive at least 1 dose of Study Drug and have at least 1 evaluable PK sample. 
10.4 
Definition of Baseline 
For fasting lipid measurements, the Baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
For other measurements, Baseline will be the last non-missing assessment prior to the first dose 
of Study Drug. 
10.5 
Interim Analysis and Early Stopping Guidelines 
Since the study is open labeled no interim analysis will be performed to inform early stopping 
guidelines.  
10.6 
Planned Methods of Analysis 
Summary tabulations will be provided for disposition, demographic, baseline, efficacy, and 
safety data as noted in the following sections. 
All eCRF data, lab data, and 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.   


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
64 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  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. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term 
and severity. 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug received will be summarized.  Patient incidence 
rates of all AEs will be tabulated by MedDRA system organ class, and by MedDRA preferred 
term.  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. 
10.6.2.2 
Clinical Laboratory Data 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, complement, etc., will be summarized by study visit.  These 
safety variables will also be presented as change and percent change from Baseline over time 
after Study Drug administration, as appropriate.  In addition, the number of subjects who 
experience abnormalities in clinical laboratory evaluations will be listed. 
10.6.2.3 
Vital Signs and Examinations 
Vital signs, weight, and ECG measures will be summarized by study visit. 
10.6.3 
Efficacy Analysis 
Change at week 27 relative to Baseline will be summarized for: 
• Fasting TG 
• MTT (plasma glucose, serum insulin, serum C-peptide, FFA, serum ghrelin, GIP, GLP-1 
and PYY) 
• Glycosylated hemoglobin  
• HOMA-IR 
• 24-hr glucose 
• Adiponectin and leptin 
• HFF 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
65 
• Fat distribution 
10.6.4 
Pharmacokinetic Analysis 
The plasma PK of ISIS 703802 (as total full length oligonucleotides, including, fully conjugated, 
partially conjugated, and unconjugated ISIS 703802) will be assessed following multiple-dose 
SC administration.  The plasma trough levels of ISIS 703802 during treatment period and those 
during post-treatment follow up period will be descriptively summarized with stratification by 
subject immunogenicity status if applicable.  
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti- ISIS 703802 antibodies) before, during, and after 
treatment with ISIS 703802 will be listed.  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 
and study day. 
 
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.  
10.6.5 
Pharmacodynamic Analysis 
The following parameters will be measured throughout the trial and change at week 27 relative 
to Baseline will be summarized: 
• 
ANGPTL3 
• HDL-C  
• LDL-C 
• TC  
• VLDL-C   
• non-HDL-C  
• apoB  
• apoB-48  
• apoB-100 
• apoA-1  
• apoC-III 
• Lp(a)  
• FFA  
• Glycerol levels 
• Lipoprotein particle size/number 
10.6.6 
Additional Analyses 
Additional analyses may be performed not specified in this open label study protocol from the 
data available. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
66 
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 or designee. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the subject or legally acceptable representative after adequate explanation 
of the aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any Study Drug ISIS 703802 are administered.  The 
subject or legally acceptable representative must be given sufficient time to consider whether to 
participate in the study.   
The acquisition of informed consent and the subject’s agreement or refusal to notify his/her 
primary care physician should be documented in the subject’s medical records and the informed 
consent form should be signed and personally dated by the subject or a legally acceptable 
representative 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 subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the informed consent 
form to the subject and must allow for questions.  Thereafter, both the subject or legally 
acceptable representative and the witness must sign the informed consent form to attest that 
informed consent was freely given and understood. 
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 subject 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 or designee before recruitment of subjects into the study and shipment of Study Drug.  
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 or designee before recruitment of 
subjects 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 SAEs occurring at the 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
67 
Study Center and other AE reports received from the Sponsor or designee, 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 or designee. 
11.4 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor or designee, subjects should be identified by 
initials (if permitted by local law) and a subject identification number only.  Documents that are 
not for submission to the Sponsor or designee (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 subject’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 subject to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the subject. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
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 subjects 
or the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee. 
12.2 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves the 
right to terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor or designee 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 or designee. 
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. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
68 
Source documents are original documents, data, and records from which the subject’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence.  Case report 
form entries may be considered source data if the case report form is the site of the original 
recording (i.e., there is no other written or electronic record of data).   
The Investigator and Study Center staff 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 or designee and/or applicable regulatory authorities.  Elements should include: 
• Subject files containing completed case report forms, 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 or designee 
• If drug supplies are maintained at the Study Center, proof of receipt, Study Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug 
product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee 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 or designee. 
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., case report forms and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms 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 subject medical records and other study-related records 
needed to verify the entries on the case report forms. 
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 case report forms, 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 (or designees).  
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. 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
69 
To ensure the quality of clinical data a clinical data management review will be performed on 
subject data received by the Sponsor or designee.  During this review, subject 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 or designee. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Whenever possible, the trade name rather than 
the generic name for concomitant medications should be recorded and if possible, in English.  
Generic names are acceptable if the trade name is unknown.  Combination medications should be 
recorded using their trade name in English if possible. 
All written information and other material to be used by subjects 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.  Subjects 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 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
70 
13. 
REFERENCES 
Ahmad Z, Subramanyam L, Szczepaniak L, Simha V, Adams-Huet B, Garg A.. Cholic acid for hepatic steatosis in 
patients with lipodystrophy: a randomized, controlled trial. Eur J Endocrinol. 2013 Apr 15;168(5):771-8. doi: 
10.1530/EJE-12-0969. Print 2013 May.  
Akinci B, Onay H, Demir T, Savas-Erdeve S, Gen R, Simsir IY, Keskin FE, Erturk MS, Uzum AK, Yaylali GF, 
Ozdemir NK, Atik T, Ozen S, Yurekli BS, Apaydin T, Altay C, Akinci G, Demir L, Comlekci A, Secil M, Oral EA. 
Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial 
lipodystrophy. Metabolism. 2017 Jul;72:109-119. doi: 10.1016/j.metabol.2017.04.010. Epub 2017 Apr 27.  
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Bidault G, Garcia M, Vantyghem MC, Ducluzeau PH, Morichon R, Thiyagarajah K, Moritz S, Capeau J, Vigouroux 
C, Béréziat V. Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro 
endothelial dysfunction. Arterioscler Thromb Vasc Biol 2013.  
Brandt TA, Lee RG, Digenio A, Graham MG, Crooke RM, Hughes SG, Singleton W, Witztum JL, Tsimikas S. 
ISIS-ANGPTL3RX, an antisense inhibitor to angiopoietin-like 3, reduces plasma lipid levels in mouse models and 
in healthy human volunteers. Atherosclerosis 2015; 241: e30-e31.  
Buller HR, Cohen AT, Davidson B, Decousus H, Gallus AS, Gent M, Pillion G, Piovella F, Prins MH, Raskob GE. 
Idraparinux versus standard therapy for venous thromboembolic disease. New England Journal of Medicine 2007; 
357: 1094-1104. 
Chan JL and Oral EA. Clinical classification and treatment of congenital and acquired lipodystrophy. Endocr Pract 
2010; 16: 310-323. Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annual Review 
of Pharmacology and Toxicology 1996; 36: 107-129. 
Diker-Cohen Cochran E, GordenT P, Brown RJ. Partial and generalized lipodystrophy: Comparison of baseline 
characteristics and response to metreleptin. J Clin Endocrinol Metab 2015.  
Diker-Cohen Cochran E, GordenT P, Brown RJ. Partial and generalized lipodystrophy: Comparison of baseline 
characteristics and response to metreleptin. J Clin Endocrinol Metab 2015. Ajluni N et al. 2016 
Dorato MA and Engelhardt JA. The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and 
definition(s). Regul Toxicol Pharmacol. 2005; 42(3): 265-74. 
Dunnigan MG, Cochrane MA, Kelly A, Scott JW. Familial lipoatrophic diabetes with dominant transmission. A new 
syndrome. Q J Med 1974; 43: 33-48.  
Everds N, Li N, Bailey K, Fort M, Stevenson R, Jawando R, Salyers K, Jawa V, Narayanan P, Stevens E, He C, 
Nguyen MP, Tran S, Doyle N, Poitout-Belissent F, Jolette J, Xu C, Sprugel K. Unexpected thrombocytopenia and 
anemia in cynomolgus monkeys induced by a therapeutic human monoclonal antibody. Toxicol Pathol. 2013; 
41(7):951-69. doi: 10.1177/0192623312474727. Epub 2013 Mar 7. 
FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for therapeutics in 
adult healthy volunteers. U.S. Department of Health and Human Services, Food and Drug Administration Center for 
Drug Evaluation and Research (CDER), July 2005. 
Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004 Mar 18; 350(12):1220-34.  
Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J J Clin Endocrinol Metab. 
2011 Nov;96(11):3313-25. doi: 10.1210/jc.2011-1159. Epub 2011 Aug 24.  
Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AA. 
Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-methoxyethyl) modified antisense 
oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 1419-1428. 
Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, Yu R, Hurh E, Paz E, McEvoy BW, Baker BF, Pham 
NC, Digenio A, Hughes SG, Geary RS, Witztum JL, Crooke RM, Tsimikas S. Cardiovascular and Metabolic Effects 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
71 
of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017 Jul 20;377(3):222-232. doi: 
10.1056/NEJMoa1701329. Epub 2017 May 24. 
Handelsman Y, Oral EA, Bloomgarden ZT, Brown RJ, Chan JL, Einhorn D, Garber AJ, Garg A, Garvey WT, 
Grunberger G, Henry RR, Lavin N, Tapiador CD, Weyer C; American Association of Clinical Endocrinologists. 
The clinical approach to the detection of lipodystrophy - An AACE Consensus Statement. Endocr Pract. 2013 Jan-
Feb;19(1):107-16  
Hegele RA. Premature atherosclerosis associated with monogenic insulin resistance. Circ 2001; 103: 2225-2229.  
Hegele RA, Joy TR, Al-Attar SA, Rutt BK. Thematic review series: Adipocyte Biology. Lipodystrophies: Windows 
on adipose biology and metabolism. J Lipid Res 2007; 48: 1433-1444.  
Henry SP, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF. Chemically modified oligonucleotides exhibit 
decreased immune stimulation in mice. J Pharmacol Exp Ther. 2000 Feb;292(2):468-79.  
Huang-Doran I, Sleigh A, Rochford JJ, O'Rahilly S, Savage DB. Lipodystrophy: metabolic insights from a rare 
disorder. J Endocrinol. 2010 Dec;207(3):245-55. doi: 10.1677/JOE-10-0272. Epub 2010 Sep 24 
Huszar D, Varban ML, Rinninger F, Feeley R, Arai T, Fairchild-Huntress V, Donovan MJ, Tall AR. Increased LDL 
cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. 
Arterioscler Thromb Vasc Biol. 2000 Apr;20(4):1068-73. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. FEBS Letters 1987 May 11; 215(2): 327-30. 
Inukai K, Nakashima Y, Watanabe M, Kurihara S, Awata T, Katagiri H, Oka Y, Katayama S. ANGPTL3 is 
increased in both insulin-deficient and -resistant diabetic states. Biochem Biophys Res Commun. 2004 May 
14;317(4):1075-9.  
Köbberling J, Willms B, Kattermann R, Creutzfeldt W. Lipodystrophy of the extremities. A dominantly inherited 
syndrome associated with lipatrophic diabetes. Humangenetik. 1975 Sep 10;29(2):111-20.  
Martin-Campos JM, Roig R, Mayoral C, Martinez S, Martí G, Arroyo JA, Julve J, Blanco-Vaca F. Identification of 
a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without 
APOB mutation. Clin Chim Acta. 2012 Mar 22;413(5-6):552-5. doi: 10.1016/j.cca.2011.11.020. Epub 2011 Nov 29. 
McKay RA, Miraglia LJ, Cummins LL, Owens SR, Sasmor H, Dean NM. Characterization of a potent and specific 
class of antisense oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem. 1999 Jan 
15;274(3):1715-22.  
Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G, Gabiati C, Pigna G, Sepe ML, Pannozzo 
F, Lütjohann D, Fazio S, Jauhiainen M, Ehnholm C, Arca M. Mutations in the ANGPTL3 gene and familial 
combined hypolipidemia: A clinical and biochemical characterization. J Clin Endocrinol Metab. 2012 
Jul;97(7):E1266-75. doi: 10.1210/jc.2012-1298. Epub 2012 Jun 1.  
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.  
Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry 
AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, 
Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S. Exome sequencing, 
ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010 Dec 2;363(23):2220-7. doi: 
10.1056/NEJMoa1002926. Epub 2010 Oct 13. 
Myalept, Package Insert 
National Organization for Rare Disorders [NORD]. The Physician’s Guide to Lipodystrophy Disorders 2012.  
Committee for Orphan Medicinal Products 2012 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
72 
Nolis T. Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. J of Human 
Gen 2014; 59:16-23.  
Noto D, Cefalu AB, Valenti V, Fayer F, Pinotti E, Ditta M, Spina R, Vigna G, Yue P, Kathiresan S, Tarugi P, 
Averna MR. Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia. 
Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):805-9. doi: 10.1161/ATVBAHA.111.238766. Epub 2012 Jan 12.  
Pisciotta L, Favari E, Magnolo L, Simonelli S, Adorni MP, Sallo R, Fancello T, Zavaroni I, Ardigò D, Bernini F, 
Calabresi L, Franceschini G, Tarugi P, Calandra S, Bertolini S. Characterization of three kindreds with familial 
combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet. 2012 Feb 
1;5(1):42-50. doi: 10.1161/CIRCGENETICS.111.960674. Epub 2011 Nov 7. 
Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, Schmidt K, Zhao C, Aghajan M, Murray HF, Riney S, 
Booten SL, Murray SF, Gaus H, Crosby J, Lima WF, Guo S, Monia BP, Swayze EE, Seth PP. Targeted delivery of 
antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in 
mice. Nucleic Acids Res. 2014 Jul;42(13):8796-807. doi: 10.1093/nar/gku531. Epub 2014 Jul 3. 
Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines DB, Gernsheimer 
TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino 
M, Watson S, Young J, Kuter DJ. International consensus report on the investigation and management of primary 
immune thrombocytopenia. Blood. 2010 Jan 14;115(2):168-86. doi: 10.1182/blood-2009-06-225565. Epub 2009 
Oct 21.  
Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH, Cohen JC. Rare loss-of-function 
mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009 
Jan;119(1):70-9. doi: 10.1172/JCI37118. Epub 2008 Dec 15. 
Robbins AL and Savage DB. The genetics of lipid storage and human lipodystrophies. Trends Mol Med. 2015 
Jul;21(7):433-8. doi: 10.1016/j.molmed.2015.04.004. Epub 2015 May 12.  
Schreyer SA, Vick C, Lystig TC, Mystkowski P, LeBoeuf RC. LDL receptor but not apolipoprotein E deficiency 
increase diet-induced obesity and diabetes in mice. Am J Physiol Endocrinol Metab. 2002 Jan;282(1):E207-14. 
Shulman, GI.  Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease N Engl J Med 2014; 
371:1131-1141. 
Sleigh A, Stears A, Thackray K, Watson L, Gambineri A, Nag S, Campi VI, Schoenmakers N, Brage S, Carpenter 
TA, Murgatroyd PR, O'Rahilly S, Kemp GJ, Savage DB. Mitochondrail oxidative phosphorylation is impaired in 
patients with congenital lipodystrophy. J Clin Endocrinol Metab. 2012 Mar;97(3):E438-42. doi: 10.1210/jc.2011-
2587. Epub 2012 Jan 11.  
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Tsuchiya H, Ikeda Y, Ebata Y, et al. Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice. 
Hepatology 2012: 56(4): 1319-1330. 
Vatier C, Bidault G, Briand N, et al. What the genetics of lipodystrophy can teach us about insulin resistance and 
diabetes. Curr Diab Rep 2013; 13 Sep (online).  
Wang Y, McNutt MC, Banfi S, Levin MG, Holland WL, Gusarova V, Gromada J, Cohen JC, Hobbs HH. Hepatic 
ANGPTL3 regulates adipose tissue energy homeostasis. Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11630-5. 
doi: 10.1073/pnas.1515374112. Epub 2015 Aug 24. 
Wang Y, McNutt MC, Banfi S, et al. Hepatic ANGPTL3 regulates adipose tissue energy homeostasis. Proc Natl 
Acad Sci USA 2015; 112:11630-11635.  
Zhang H, Löwenberg EC, Crosby JR, MacLeod AR, Zhao C, Gao D, Black C, Revenko AS, Meijers JC, Stroes ES, 
Levi M, Monia BP. Inhibition of the intrinsic coagulation pathway Factor XI by antisense oligonucleotides: a novel 
antithrombotic strategy with lowered bleeding risk. Blood. 2010 Nov 25;116(22):4684-92. doi: 10.1182/blood-2010-
04-277798. Epub 2010 Aug 31.  
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
73 
 
 
 
 
 
 
 
14. 
APPENDICES 
.


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
09 November 2017 
 
74 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
 
 
 
 
 
 
 
 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
06 November 2017 
 
75 
Appendix A  Schedule of Procedures  
 
 
 
Screening 
 
Treatment Period 
Follow-up Period 
Diet Run-
in# 
Qual† 
Study Week 
-6 to -1 
-1 to 0 
1 
5 
9 
13 
17 
21 
25 
27/ET 
4* 
8* 
13* 
Study Day 
-42 to -1 
-7 to -1 
1 
29 
57 
85 
113 
141 
169 
183 
*Post Last Dose of Study 
Drug 
Visit and Testing Window +/- Days 
0 
0 
0 
2 
2 
2 
3 
3 
3 
0 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination a 
X 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
Body Weight and Height b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist and hip circumference 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
DEXA Scan 
Xd 
 
 
 
X 
 
 
 
X 
 
 
 
12- lead ECG (triplicate) 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Ultrasound  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Mixed Meal Test c 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
MRI  
Xd 
 
 
 
X 
 
 
 
X 
 
 
 
24-Hour Urine for Creatinine 
Clearance and Protein 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Extended Urinalysis e 
X 
 
EVERY 14 DAYS (+/- 2 days) e, f 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine and Cys-C i, j, k 
X 
 
EVERY 14 DAYS (+/- 2 days) f, i 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel j , k 
X 
 
EVERY 14 DAYS (+/- 2 days) f 
X 
X 
X 
X 
X 
X 
X 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
06 November 2017 
 
76 
Appendix A  Schedule of Procedures Continued 
# Subjects on stable diet known to the investigator and followed at the site may go from Screening to qualification without the diet run-in period. 
† Qual =Qualification  
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
Full physical exam will be performed at the screening visit and an abbreviated physical exam will be performed during treatment and follow-up periods. 
b     Height only required at Screening 
c     Mixed Meal Test-refer to Appendix E for further details 
d     MRI and DEXA scan will only be performed after subjects have met initial screening eligibility.  MRI and DEXA scan should be performed as close to 
anticipated Day 1 date as possible and to allow time for result reporting and analysis. 
Visit and Testing Window +/- Days 
0 
0 
0 
2 
2 
2 
3 
3 
3 
0 
3 
3 
3 
Hematology 
X 
 
EVERY 14 DAYS (+/- 2 days) f 
Xh 
Xh 
Xh 
Coagulation 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Liver Biomarkers 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 703802 l 
 
 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
X 
Anti-ISIS 703802 Antibodies 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
FSH (women only, if applicable) j, m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test m 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Archived Serum & Plasma Samples 
j, n 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
PD Panel j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Extended Lipid Panel j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1C j 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Quality of Life Assessment 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Widespread Pain Diary 
 
X 
TO BE DONE AT OUTPATIENT VISITS  
X 
X 
X 
Study Drug:  SC Injection 
 
 
WEEKLY SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 
through Week 26/Day 176) 
 
 
 
 
Adverse Events 
TO BE COLLECTED FROM TIME OF INFORMED CONSENT TO END OF FOLLOW-UP PERIOD 
Concomitant Medication 
TO BE COLLECTED FROM TIME OF INFORMED CONSENT TO END OF FOLLOW-UP PERIOD 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
06 November 2017 
 
77 
Appendix A  Schedule of Procedures Continued 
e 
All tests listed in Appendix B under Extended Urinalysis should be performed, including routine urinalysis, urine microscopy, UACR and UPCR. 
f 
Assessments and procedures to be conducted by either a home healthcare service or the Study Center.  Subject Study Center visits must be no more than 
4 weeks apart during the treatment period. 
g 
Urine samples for renal biomarkers will be collected.  Sample analysis will be conducted in accordance with Safety Monitoring for Renal Function 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values are taken every 14 days (+/- 2 days) for 6 weeks after last dose of Study Drug, then at Week 
8 and Week 13 Follow-up visits.   
i 
Serum Creatinine and Cys-C will be collected as a part of chemistry panel at visits when chemistry panel is performed, or as stand-alone samples at time 
points when a chemistry panel is not performed. 
j 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours, unless tests are repeated for safety reasons. 
k 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen should be re-drawn as soon as possible (ideally within 7 days).  All platelet count results will be reviewed promptly (within 48 hours of receipt) by the 
Investigator as per Section 6.2.1.  Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
l      Refer to Appendix C for PK Sampling schedule. 
m 
Women who are not surgically sterile or post-menopausal. 
n 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or 
chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) and will be retained until completion of the final 
study report. 
 
Time (time is in reference to Study Drug administration): 
1 Pre-dose 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
78 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
79 
Appendix B List of Laboratory Analytes 
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 
• 
Creatinine kinase 
• 
GGT 
• 
Cys-C 
 
PD Panel 
• 
ANGPTL3 
• 
Insulin 
• 
Proinsulin 
• 
C-peptide 
• 
Fructosamine 
• 
Glycated albumin 
• 
Delipidated Free Glycerol 
• 
Fasting Plasma Glucose 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Screening Tests 
• 
Hepatitis B 
surface antigen 
• 
Hepatitis C 
antibody 
• 
HIV antibody 
• 
FSH (women 
only) 
• 
Serum βhCG 
• 
TSH 
• 
Free T4 
 
 
Extended Lipid  Panel 
• 
Total Cholesterol 
(TC) 
• 
LDL cholesterol 
(LDL-C) 
• 
HDL cholesterol 
(HDL-C) 
• 
Triglycerides (TG) 
• 
VLDL cholesterol 
(VLDL-C) 
• 
Non-HDL 
cholesterol (Non-
HDL-C) 
• 
Lp(a) 
• 
FFA 
• 
ApoB 
• 
ApoB-48 
• 
ApoB-100 
• 
Apo A-1 
• 
ApoCIII (total, 
chylomicron, 
LDL, HDL, 
VLDL) 
• 
Delipidated Free 
Glycerol 
• 
Ceramides 
• 
Sphingolipids 
• 
Diacyglycerol 
• 
Lipoprotein 
particle analysis 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, MCHC 
• Platelets 
• White blood cells 
• WBC Differential (% and 
absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Pharmacokinetics1 
• ISIS 703802 levels in 
plasma 
 
Immunogenicity 
• Anti-ISIS 703802 
antibodies 
 
Liver Biomarkers (Biomarkers 
of liver apoptosis and fibrosis) 
• CK18  
• PIIINP  
 
Inflammatory 
• hs-CRP 
• IL-6 
• IFN gamma 
• TNF alpha 
• Leptin 
• Adiponectin 
 
Genetic Testing 
• Genetic sequencing of FPL 
causing genes3 
 
Extended Urinalysis 
• 
Routine Urinalysis 
- 
Color 
- 
Appearance 
- 
Specific gravity 
- 
pH 
- 
Protein 
- 
Blood 
- 
Glucose 
- 
Ketones 
- 
Bilirubin 
- 
Urobilinogen 
- 
Leukocyte esterase 
- 
Nitrate 
• 
Microscopic examination 
• 
P/C Ratio (UPCR) 
• 
A/C Ratio (UACR) 
 
24-Hour Urine Test 
• 
Creatinine clearance 
• 
Protein 
• 
Albumin 
 
Mixed Meal Test 
• 
Plasma glucose 
• 
FFA 
• 
C-peptide 
• 
Insulin 
• 
Serum ghrelin 
• 
GIP 
• 
GLP-1 
• 
PYY 
• 
Incretin hormones 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation purposes, 
stability assessments, metabolite assessments, or to assess other actions of ISIS 703802 with plasma constituents 
2 
All samples will be collected, handled and stored under the conditions specified for the assays. Please refer to the study 
Laboratory Manual for details on the appropriate handling and storage methods for biomarker and other samples. 
3 
Blood will be collected to assess genetic evidence of FPL (e.g., mutations in LMNA, PPAR-γ, AKT2, CIDEC, PLIN1 
genes).  May not be collected if adequate genetic data are available in medical history or if patient does not consent to 
genetic testing 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
80 
 
 
 
 
 
Appendix C 
PK Sampling Schedule  
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
81 
Appendix C PK Sampling Schedule  
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
5 
9 
13 
17 
21 
25 
27 
4* 
8* 
13* 
Study 
Day 
D1 
D29 
D57 
D85 
D113 
D141 
D169 
D183 
*Post Last Dose of Study Drug 
 
 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
Anytime 
Anytime 
Note:  D, Day 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
82 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
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 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
84 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
85 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
86 
 
 
 
 
 
 
 
 
 
 
Appendix E 
Mixed Meal Test 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Original 
Protocol 
 
07 November 2017 
 
87 
Appendix E Mixed Meal Test  
At Baseline, 3 months and end of study, subjects enrolled will undergo a meal tolerance test 
(MTT) as follows: subjects will consume a standardized meal the evening before the test        
(750 kcal; 20% of energy from protein, 30% from fat, and 50% from carbohydrate) and refrain 
from consuming alcohol for 72 h.  
A cannula will be inserted into a forearm vein, and an overnight fasting venous blood sample 
will be taken between 8:00 AM and 10:00 AM for measurement of plasma glucose, FFA,         
C-peptide and insulin concentrations and serum ghrelin, GIP, GLP-1, and PYY.  Incretin 
hormones will be measured using a multiplex assay (EMD Millipore, Billerica, MA).  The tubes 
for the incretin hormones will contain Pefabloc SC (Sigma-Aldrich, St. Louis, MO) and DPP-IV 
inhibitor (EMD Millipore, Billerica, MA) to inhibit DPP-IV and other proteases.  The change in 
ratings from Baseline will be quantified.  
Subjects will then consume a liquid load of Optifast (Optifast; Novartis, Minneapolis, MN;        
474 ml, 320 kcal, 50% carbohydrate, 35% protein, 15% fat) within a 15-min period.  Additional 
blood samples will be taken at 10, 20, 30, 60, 90, 120, 150, 180, 240 and 300 min after meal 
consumption.  VAS will be completed at 180 minutes and 300 min.  To calculate the insulin 
sensitivity index (SI), the oral minimal model for glucose will be used; and to calculate the 
hepatic insulin extraction, oral minimal model for insulin and c-peptide will be used [Cobelli et 
al, 2007; Cobelli et al, 2005]. Subjects will complete a validated visual analogue scale 
(VAS) questionnaire to assess subjective hunger at 0, 180 and 300 minutes [Luscombe-Marsh et 
al, 2005; Moran et al, 2005]. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
1 
             
 
Sponsor: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
 
 
 
 
ISIS 703802-CS5 
 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
 
Amendment 1 – 16 February 2018 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
2 
 
 
 
ISIS 703802-CS5 
 
 
 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-
ANGPTL3-LRx) Administered Subcutaneously to Subjects 
with Familial Partial Lipodystrophy 
Amendment 1 – 16 February 2018 
Protocol History 
Original Protocol            09 November 2017 
Protocol Amendment 1   16 February 2018 
 
 
_ 
, MD, FACP  
  
Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Telephone: (617) 207-0202 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
3 
ISIS 703802 
Protocol Number ISIS 703802-CS5 
Amendment 1 
 
Clinical Phase:  2 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-
LRx) Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
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: 
 
E-mail: 
 
 Sponsor Medical Monitor: 
, MD 
 - Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Phone:
Mobile: 
 
E-mail:
 
 
Date: 
16 February 2018 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. and 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 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
4 
Protocol Signature Page 
 
Protocol Number:         ISIS 703802-CS5 
Protocol Title: 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
 Amendment: 
Amendment 1 
Date:                              16 February 2018 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An open-
label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered Subcutaneously to Subjects 
with Familial Partial Lipodystrophy” dated 16 February 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). 
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 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
5 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ......................................................................................................................... 21 
STUDY DESIGN AND TREATMENT SCHEMA ................................................................................ 27 
STUDY GLOSSARY ................................................................................................................................ 28 
1. 
OBJECTIVES .............................................................................................................................. 32 
1.1 
Primary Objective ...................................................................................................................... 32 
1.2 
Secondary Objective(s) ............................................................................................................. 32 
2. 
BACKGROUND AND RATIONALE ....................................................................................... 32 
2.1 
Overview of Disease.................................................................................................................. 32 
2.2 
Therapeutic Rationale ................................................................................................................ 35 
2.3 
ISIS 703802 ............................................................................................................................... 35 
2.3.1 
Mechanism of Action ........................................................................................................ 35 
2.3.2 
Chemistry .......................................................................................................................... 36 
2.3.3 
Preclinical Experience ....................................................................................................... 37 
2.3.3.1 
Preclinical Pharmacology ........................................................................................... 37 
2.3.3.2 
Preclinical Toxicology ............................................................................................... 38 
2.3.4 
Clinical Experience ........................................................................................................... 39 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD ....................................................................... 40 
2.4 
Rationale for Dose and Schedule of Administration ................................................................. 40 
2.5 
Benefit-Risk Assessment ........................................................................................................... 40 
2.5.2 
Risk Assessment ................................................................................................................ 40 
2.5.3 
Overall Assessment of Benefit: Risk ................................................................................. 42 
3. 
EXPERIMENTAL PLAN ........................................................................................................... 42 
3.1 
Study Design ............................................................................................................................. 42 
3.2 
Number of Study Centers .......................................................................................................... 43 
3.3 
Number of Subjects ................................................................................................................... 43 
3.4 
Overall Study Duration and Follow-up ..................................................................................... 43 
3.4.1 
Screening/Qualification ..................................................................................................... 43 
3.4.2 
Treatment .......................................................................................................................... 43 
3.4.3 
Post-Treatment .................................................................................................................. 43 
4. 
SUBJECT ENROLLMENT ........................................................................................................ 43 
4.1 
Screening ................................................................................................................................... 43 
4.2 
Registration ............................................................................................................................... 44 
4.3 
Replacement of Subjects ........................................................................................................... 44 
5. 
SUBJECT ELIGIBILITY ........................................................................................................... 44 
5.1 
Inclusion Criteria ....................................................................................................................... 44 
5.2 
Exclusion Criteria ...................................................................................................................... 46 
6. 
STUDY PROCEDURES ............................................................................................................. 48 
6.1 
Study Schedule .......................................................................................................................... 48 
6.1.1 
Screening/Qualification ..................................................................................................... 48 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
6 
6.1.2 
Treatment Period ............................................................................................................... 48 
6.1.3 
Post-Treatment Period ....................................................................................................... 49 
6.2 
Study/Laboratory Assessments ................................................................................................. 49 
6.2.1 
Physical Exams and Vital Signs ........................................................................................ 50 
6.2.2 
DEXA Scan ....................................................................................................................... 50 
6.2.3 
Electrocardiography .......................................................................................................... 50 
6.2.4 
PK Sampling ..................................................................................................................... 50 
6.2.5 
Mixed Meal Test ............................................................................................................... 50 
6.2.6 
MRI 
 ............................................................................................................................ 51 
6.3 
Restriction on the Lifestyle of Subjects ..................................................................................... 51 
6.3.1 
Contraception Requirements ............................................................................................. 51 
6.3.2 
Other Requirements ........................................................................................................... 52 
7. 
STUDY DRUG ............................................................................................................................. 52 
7.1 
ISIS 703802 ....................................................................................................................... 52 
7.2 
Packaging and Labeling ............................................................................................................ 52 
7.3 
Study Drug Accountability ........................................................................................................ 52 
8. 
TREATMENT OF SUBJECTS .................................................................................................. 53 
8.1 
Study Drug Administration ....................................................................................................... 53 
8.2 
Other Protocol-Required Drugs ................................................................................................. 53 
8.3 
Other Protocol-Required Treatment Procedures ....................................................................... 53 
8.4 
Treatment Precautions ............................................................................................................... 53 
8.5 
Safety Monitoring Rules ............................................................................................................ 53 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ......................................................... 54 
8.5.2 
Safety Monitoring for Renal Function .............................................................................. 55 
8.5.3 
Safety Monitoring Rules for Platelet Count Results ......................................................... 56 
8.5.4 
Safety Monitoring for Bleeding Events ............................................................................. 57 
8.5.5 
Safety Monitoring for Constitutional Symptoms .............................................................. 57 
8.5.6 
Safety Monitoring for Hypoglycemia ............................................................................... 57 
8.5.7 
Safety Monitoring for Documented Hyperglycemia ......................................................... 58 
8.6 
Stopping Rules .......................................................................................................................... 60 
8.6.1 
Stopping Rules for Liver Chemistry Elevations ................................................................ 60 
8.6.2 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for Renal 
Function Test Results ........................................................................................................ 60 
8.6.3 
Stopping Rule for Platelet Count Results .......................................................................... 61 
8.7 
Adjustment of Dose and/or Treatment Schedule ....................................................................... 63 
8.8 
Discontinuation of Study Drug/Treatment ................................................................................ 63 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from Post-Treatment 
Follow-up Period ............................................................................................................... 63 
8.9 
Withdrawal of Subjects from the Study .................................................................................... 64 
8.10 
Concomitant Therapy and Procedures ....................................................................................... 64 
8.10.1 
Concomitant Therapy ........................................................................................................ 64 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
7 
8.10.2 
Concomitant Procedures .................................................................................................... 65 
8.11 
Treatment Compliance .............................................................................................................. 65 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................... 65 
9.1 
Sponsor Review of Safety Information ..................................................................................... 65 
9.2 
Regulatory Requirements .......................................................................................................... 65 
9.3 
Definitions ................................................................................................................................. 66 
9.3.1 
Adverse Event ................................................................................................................... 66 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ......................................................... 66 
9.3.3 
Serious Adverse Event (SAE) ........................................................................................... 66 
9.3.3.1 
Adverse Events of Special Interest ............................................................................. 67 
9.4 
Monitoring and Recording Adverse Events .............................................................................. 67 
9.4.1 
Serious Adverse Events ..................................................................................................... 67 
9.4.2 
Non-Serious Adverse Events ............................................................................................. 67 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ................................................ 67 
9.4.3.1 
Relationship to the Study Drug .................................................................................. 68 
9.4.3.2 
Severity....................................................................................................................... 68 
9.4.3.3 
Action Taken with Study Drug .................................................................................. 68 
9.4.3.4 
Treatment Given for Adverse Event........................................................................... 69 
9.4.3.5 
Outcome of the Adverse Event .................................................................................. 69 
9.5 
Procedures for Handling Special Situations .............................................................................. 69 
9.5.1 
Abnormalities of Laboratory Tests .................................................................................... 69 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ....................... 70 
9.5.3 
Dosing Errors .................................................................................................................... 70 
9.5.4 
Contraception and Pregnancy ............................................................................................ 70 
10. 
STATISTICAL CONSIDERATIONS ....................................................................................... 71 
10.1 
Study Endpoints, Subsets, and Covariates................................................................................. 71 
10.1.1 
Primary Endpoint .............................................................................................................. 71 
10.1.2 
Secondary Endpoints ......................................................................................................... 71 
10.2 
Sample Size Considerations ...................................................................................................... 71 
10.3 
Populations ................................................................................................................................ 71 
10.4 
Definition of Baseline................................................................................................................ 72 
10.5 
Interim Analysis and Early Stopping Guidelines ...................................................................... 72 
10.6 
Planned Methods of Analysis .................................................................................................... 72 
10.6.1 
Demographic and Baseline Characteristics ....................................................................... 72 
10.6.2 
Safety Analysis .................................................................................................................. 72 
10.6.2.1 
Adverse Events ........................................................................................................... 72 
10.6.2.2 
Clinical Laboratory Data ............................................................................................ 72 
10.6.2.3 
Vital Signs and Examinations .................................................................................... 73 
10.6.3 
Efficacy Analysis .............................................................................................................. 73 
10.6.4 
Pharmacokinetic Analysis ................................................................................................. 73 
10.6.5 
Pharmacodynamic Analysis .............................................................................................. 74 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
8 
10.6.6 
Additional Analyses .......................................................................................................... 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 
Subject 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 .............................................................................................................................. 82 
Appendix A  
Schedule of Procedures .............................................................................................. 83 
Appendix B 
 List of Laboratory Analytes ...................................................................................... 87 
Appendix C 
 PK Sampling Schedule .............................................................................................. 89 
Appendix D 
 Grading Scale for Adverse Events Relating to Laboratory Abnormalities ............... 91 
Appendix E 
 Mixed Meal Test ....................................................................................................... 95 
Appendix F 
 Laboratory Tests to Be Performed in the Event of a Platelet Count ˂ 100,000/mm3 97 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ............................................................................................... 52 
Table 2 
Study Drug Dosing Information ....................................................................................... 53 
Table 3 
Actions in Subjects with Low Platelet Count ................................................................... 62 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  (MOE-
Gapmer).  The sequence of ISIS 703802 is shown. .......................................................... 37 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
9 
 
PROTOCOL AMENDMENT  
Protocol Number:         ISIS 703802-CS5 
Protocol Title: 
An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-
LRx) Administered Subcutaneously to Subjects with Familial Partial 
Lipodystrophy 
Amendment Number:  Protocol Amendment 1 
Amendment Date:        16 February 2018 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol ISIS 
703802-CS5 Original Protocol dated 09 November 2017 intended to clarify inconsistencies, make some 
administrative updates and add an appendix. The following administrative updates have been made: 
Akcea Therapeutics, Inc. now appears as the Sponsor and Ionis Pharmaceuticals, Inc. now appears as the 
Collaborator; ISIS 703802-CS05 is being updated to ISIS 703802-CS5. In addition, the reference list has 
been updated. The tables being updated are not shown in this summary of changes. Finally, minor updates 
noted as inconsistencies have been made throughout the document. Note that language in the Was section 
that is being deleted appears as strikethrough and new language in the Update section appears as bold:  
1. Synopsis and Section 5.2 Exclusion Criteria number 6 
Was:  
6. History of heart failure with New York Heart Association functional classification (NYHA) 
greater than Class II or unstable congestive cardiac failure requiring a change in medication 
Update:  
6. History of heart failure with New York Heart Association functional classification (NYHA) 
greater than Class II  
Rationale: 
The portion of exclusion criterion 6 that is being deleted is covered in exclusion criterion 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 heart 
failure requiring a change in medication 
2. The following changes have been made to several sections with respect to MRI and DEXA 
scan 
Synopsis sections Study Visit Schedule and Procedures 
Was: 
Subjects on stable diet known to the investigator and followed at the site may go from Screening to 
qualification without a 4-week diet run-in. TGs will be measured and. MRI will be obtained to assess 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
10 
liver fat content.  For subjects who are already on a stable diet and are known to the site, the diet 
stabilization period can be omitted and subject can move directly to qualification. 
Update: 
Subjects on stable diet known to the investigator and followed at the site may go from Screening to 
qualification without a 4-week diet run-in. At the qualification visit TGs will be measured. MRI and 
DEXA scan will be obtained during screening once all other eligibility criteria are met to assess 
liver fat content.   
Section 3.1 Study Design end of paragraph two 
Was: 
At the qualification visit TGs will be measured to qualify and MRI will be obtained to assess liver fat 
content.  MRI results must be available prior to registration and administration of the first dose of 
study drug. 
Update: 
At the qualification visit TGs will be measured.  MRI and DEXA scan will be obtained during 
screening once all other eligibility criteria are met to assess liver fat content.  MRI results must be 
available prior to registration and administration of the first dose of study drug. 
Section 3.4.1 Screening/Qualification end of paragraph one 
Was: 
At the qualification visit subjects will have a baseline DEXA scan and MRI will be obtained to assess 
liver fat content.  MRI results must be available prior to registration and administration of the first 
dose of study drug. 
Update: 
At the qualification visit TGs will be measured.  A baseline DEXA scan and MRI will be obtained 
to assess liver fat content once all other eligibility has been confirmed.  MRI results must be 
available prior to registration and administration of the first dose of study drug. 
Section 6.1.1 Screening/Qualification end of paragraph three 
Was: 
At the qualification visit TGs will be measured and MRI will be obtained to assess liver fat content.  
MRI results must be available prior to registration and administration of the first dose of study drug. 
Update: 
At the qualification visit TGs will be measured. MRI and DEXA scan will be obtained during 
screening once all other eligibility criteria are met to assess liver fat content.  MRI results must be 
available prior to registration and administration of the first dose of study drug. 
Section 6.2.6 MRI 
Was: 
An MRI to determine liver fat fraction will be done at Qualification, Week 13 and Week 27.  
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
11 
Update: 
An MRI to determine liver fat fraction will be done during Screening after all other eligibility 
criteria are met, and again at Week 13 and Week 27.  
Appendix A Footnote d 
Was: 
d     MRI and DEXA scan will only be performed after subjects have met initial screening eligibility. 
MRI and DEXA scan should be performed as close to anticipated Day 1 date as possible and to 
allow time for result reporting and analysis. 
Update: 
d     MRI and DEXA scan will only be performed during Screening after all other eligibility 
criteria are met.  MRI should be performed 10 days (+/- 2 days) prior to anticipated Day 1 
date to allow time for result reporting and analysis.  DEXA scan should be performed as close 
to anticipated Day 1 date as possible. 
Rationale:  
The MRI and DEXA scan should be performed after all other eligibility criteria are met and as close 
to day 1 as possible, allowing for sufficient time to turn around results. 
3. Section 4 Subject Enrollment 
 
A. Was: 
 
Subjects must sign the consent form before any screening tests or assessments are performed.  At the 
time of consent, the subject will be considered enrolled into the Study and will be assigned a unique 
subject identification number before any study procedures, including screening procedures, are 
performed. 
 
A. Update: 
 
Subjects must sign the consent form before any screening tests or assessments are performed.  At the 
time of consent, the subject will be considered screened into the Study and will be assigned a unique 
subject identification number before any study procedures, including screening procedures, are 
performed. 
 
B. Was: 
 
Subjects will be registered after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No subject may 
begin treatment prior to assignment of a unique subject identification number. 
 
B. Update: 
 
Subjects will be registered after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  Once a subject is 
registered for the study, they are considered enrolled into the study.  No subject may begin 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
12 
treatment prior to assignment of a unique subject identification number nor confirmation of 
eligibility. 
 
Rationale: 
 
These changes are meant to clarify screening and enrollment into the study. 
 
4. Section 6.2 Study/Laboratory Assessments paragraph eight 
Was: 
All lab samples sent to the central laboratory are received on the next day and processed.  Lab Alerts 
issued as per protocol safety monitoring requirements or stopping rules will indicate the applicable 
protocol section to facilitate review and will be immediately and simultaneously sent by email to the 
Investigator, the Sponsor and the CRO Medical Monitors, the Sponsor Drug Safety Physician, and the 
Clinical Trial Manager (CTM), and should be received by them within 2 days from sample collection.  
Hematology results from the site’s local laboratories are received by the study center staff on the day 
of sample collection, and should be entered as soon as possible into the eCRF to inform the Sponsor 
and CRO study monitoring teams.  
Update: 
All lab samples are to be sent to the central laboratory by overnight courier and processed.  Lab 
Alerts issued as per protocol safety monitoring requirements or stopping rules will indicate the 
applicable protocol section to facilitate review and will be immediately and simultaneously sent by 
email to the Investigator, the Sponsor and the CRO Medical Monitors, the Sponsor Drug Safety 
Physician, and the Clinical Trial Manager (CTM), and should be received by them within 2 days from 
sample collection.  Hematology results from the site’s local laboratories are received by the study 
center staff per the local laboratory’s standard reporting time, and should be entered as soon as 
possible into the eCRF to inform the Sponsor and CRO study monitoring teams.  
Rationale: 
There could be reasons why samples sent to the central lab are not received the following day. The 
local laboratory will provide results on specimens tested within its standard timeframe. 
5. The following changes have been made to several sections with respect to renal function  
Section 8.5.2 Safety Monitoring for Renal Function paragraph three and six 
A. Was:  
While on treatment during the course of the study, urinary surveillance may include urinalysis to 
include urine albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and urinary red 
blood cells (RBCs), as well as serum creatinine and cystatin-C to estimate glomerular filtration rate 
(eGFR) which will be monitored every 2 weeks during the first 3-months of the study treatment 
period, and monthly thereafter.  In addition, other biomarkers of acute renal injury may also be 
measured if a safety signal is seen that warrants further testing.  (Appendix B).  
A. Update: 
While on treatment during the course of the study, urinary surveillance may include urinalysis to 
include urine albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and urinary red 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
13 
blood cells (RBCs), as well as serum creatinine and cystatin-C which will be monitored every 2 
weeks during the first 3-months of the study treatment period, and monthly thereafter.  In addition, 
other biomarkers of acute renal injury may also be measured if a safety signal is seen that warrants 
further testing.  (Appendix B).  
B. Was: 
Lab alerts for abnormal renal tests will be issued for:  Creatinine clearance (by CKD-EPI formula) 
decrease from Baseline > 25%, urine albumin/creatinine ratio (UACR) > 250 mg/g, urine 
protein/creatinine ratio (UPCR) > 0.5 mg/mg, or an increase in serum creatinine from Baseline > 0.3 
mg/dL). 
B. Update: 
Lab alerts for abnormal renal tests will be issued for: eGFR (by CKD-EPI formula) decrease from 
Baseline > 25%, urine albumin/creatinine ratio (UACR) > 250 mg/g, urine protein/creatinine ratio 
(UPCR) > 0.5 mg/mg, or an increase in serum creatinine from Baseline > 0.3 mg/dL). 
Section 8.6.2 Stopping Rules for Renal Function Test Results/Temporary Stopping Rules for Renal 
Function Test Results 
 
Was: 
In the event of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the following 
criteria, or any change in renal biomarkers deemed by the nephrologist to require further evaluation, a 
serum creatinine and 24-hour urine sample for creatinine clearance and protein should be obtained: 
1. CKD-EPI decrease of > 40% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Update: 
In the event of an eGFR (by CKD-EPI formula) meeting any of the following criteria, or any change 
in renal biomarkers deemed by the nephrologist to require further evaluation, a serum creatinine and 
24-hour urine sample for creatinine clearance and protein should be obtained: 
1. eGFR (CKD-EPI) decrease of > 40% from Baseline 
2. eGFR (CKD-EPI) value < 45 mL/min/1.73 m2 
Synopsis and Section 5.2 Exclusion Criteria number 8 paragraph b 
Was:  
Estimated GFR ˂ 60 mL/min (as determined by the Chronic Kidney Disease-Epidemiological 
Collaboration (CKD-EPI) Equation for creatinine clearance 
Update:  
Estimated GFR ˂ 60 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation  
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
14 
Rationale:  
These changes are made to consistently identify estimated glomerular filtration rate as measured by 
CKD-EPI formula and avoid confusion with creatinine clearance in the protocol.  
6. The following changes have been made to several sections with respect to platelet 
monitoring  
Section 8.5.3 Safety Monitoring Rules for Platelet Count Results paragraph three and six 
A. Was: 
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is considered 
an adverse event of special interest and should be reported in an expedited fashion to the Sponsor.  
A. Update: 
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is considered 
an adverse event of special interest and should be reported in an expedited fashion to the Sponsor. In 
this case, the Investigator should refer the subject to a hematologist to provide diagnostic and 
therapeutic management. 
B. Was: 
In the event of a platelet count ˂ 100,000/mm3 the laboratory tests outlined in Table 3, should be 
performed as soon as possible.  Additional lab tests will be determined by the Sponsor Medical 
Monitor or designee in consultation with the Investigator.  
B. Update: 
In the event of a platelet count ˂ 100,000/mm3, the laboratory tests outlined in Table 3 should be 
performed as soon as possible.  In addition to action taken as outlined in Table 3, in the event of a 
platelet count <100,000/mm3, tests outlined in Appendix F should be performed as soon as 
possible. Additional lab tests, if warranted, will be determined by the Sponsor Medical Monitor or 
designee in consultation with the Investigator.  
Section 8.6.3 Stopping Rule for Platelet Count Results  
The greater than or equal sign (>) has been added to a couple of places in the fourth paragraph in 
order to align with updates in Table 3. In addition, paragraph six: 
Was: 
Once a subject commences weekly monitoring, this frequency of monitoring should continue 
irrespective of whether the platelet count rises into the normal range.  
Update: 
Once a subject commences weekly monitoring, this frequency of monitoring should continue until 
the platelet count returns to the normal range (>140,000/mm3) for 2 successive values. 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
15 
Table 3 Actions in Subjects with Low Platelet Count during Treatment or Post-Treatment Period 
Was: 
Footnote: Once a subject commences weekly monitoring this frequency of monitoring should 
continue irrespective of whether the platelet count rises into the normal range. 
Update: 
Footnote: Once a subject commences weekly monitoring this frequency of monitoring should 
continue until the platelet count returns to the normal range (> 140,000/mm3) for 2 successive 
values. 
Rationale:  
Several changes have been made to Table 3 in order to clarify normal ranges, to clarify the need to 
refer Grade 3 and 4 low platelet counts to a hematologist and to clarify when to start and when to 
discontinue weekly platelet monitoring.  
Appendix F Additional testing for low platelet count 
Addition of a table outlining tests to be performed on patients that experience a single occurrence of 
platelets <100,000/mm3.  
Rationale: 
Changes have been made in order to clarify normal ranges, to clarify the need to refer Grade 3 and 4 
low platelet counts to a hematologist, and to clarify when to start and when to discontinue weekly 
platelet monitoring. These changes are expected to help better understand the reasons for platelet 
count reductions, were they to occur, and ensure close monitoring of subjects if a single platelet count 
reduction <100,000/mm3 is observed. These changes are also expected to ensure continuity of safety 
monitoring for subjects with a decreased platelet count.  
7. Section 8.5.4 Safety Monitoring for Bleeding Events and Section 8.6.3 Stopping Rule for 
Platelet Count Results 
 
These sections have been re-arranged in such a way that monitoring of bleeding events has been taken 
out of Section 8.6.3 and added to Section 8.5.4. 
  
The following has been deleted from Section 8.5.4 due to the redundancy resulting from the re-
arrangement above: 
 
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, or 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, hepatic 
enzymes, bilirubin and platelet count may be performed. 
 
The following was deleted from Section 8.5.4 to avoid protocol deviations: 
 
Patients will be instructed to promptly report any signs or symptoms of bleeding.  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
16 
 
In addition, Section 8.5.4 has an additional phrase and sentence:  
 
Was: 
Subjects will be evaluated for occurrence of bleeding events continuously after the start of Study 
Drug treatment (Day 1)  
 
Update: 
Subjects will be evaluated for occurrence of bleeding events continuously after the start of Study 
Drug treatment (Day 1) up to the end of the follow-up period for all cohorts.  All bleeding events 
are considered adverse events and reported on adverse event case report form. 
 
Rationale: 
Monitoring and the monitoring period have been clarified and clarification that bleeding events are to 
be considered adverse events has been added. 
 
8. Section 8.5.6 Safety Monitoring for Hypoglycemia 
Was:  
The alert value for hypoglycemia is ≤ 70 mg/dL (≤ 3.9 mmol/L) plasma concentration. 
Severe Hypoglycemia 
Requires assistance of another person to actively administer carbohydrates, glucagon, or take other 
corrective actions. Plasma glucose concentrations may not be available during an event. Neurological 
recovery following plasma glucose levels returning to normal considered sufficient evidence that 
event was induced by low plasma glucose concentration. 
Documented Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms accompanied by measured plasma glucose ≤ 70 mg/dL (≤ 3.9 
mmol/L).  
Asymptomatic Hypoglycemia  
Not accompanied by typical hypoglycemia symptoms but with measured plasma glucose≤ 70 mg/dL 
(≤ 3.9 mmol/L). 
Probable Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms not accompanied by plasma glucose determination but likely caused 
by plasma glucose ≤ 70 mg/dL (≤ 3.9 mmol/L). 
A documented severe hypoglycemic event is defined as one in which the subject 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. 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
17 
Update:  
The alert value for hypoglycemia is ≤ 70 mg/dL (≤ 3.9 mmol/L) blood glucose concentration. 
Severe Hypoglycemia 
Requires assistance of another person to actively administer carbohydrates, glucagon, or take other 
corrective actions. Glucose concentrations may not be available during an event. Neurological 
recovery following glucose levels returning to normal considered sufficient evidence that event was 
induced by low glucose concentration. 
Documented Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms accompanied by measured blood glucose ≤ 70 mg/dL (≤ 3.9 
mmol/L).  
Asymptomatic Hypoglycemia  
Not accompanied by typical hypoglycemia symptoms but with measured blood glucose≤ 70 mg/dL 
(≤ 3.9 mmol/L). 
Probable Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms not accompanied by blood glucose determination but likely caused 
by blood glucose ≤ 70 mg/dL (≤ 3.9 mmol/L). 
A documented severe hypoglycemic event is defined as one in which the subject requires assistance 
of another person to obtain treatment for the event and has a blood glucose level ≤ 70 mg/dL 
(≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or buccal or 
intramuscular glucagon. 
Rationale:  
Determination of severe hypoglycemia can be measured by glucometer. Therefore, the language has 
been made more generic. 
9. Section 8.5.7 Safety Monitoring for Documented Hyperglycemia 
A. Was:  
From baseline visit to Week 13 (including value at Week 13) of Randomized Treatment period: 
• 
FPG > 270 mg/dL (15.0 mmol/L) 
From Week 13 to Week 25/27/ET (including value at Week 25/27/ET) of Randomized Treatment 
period: 
• 
FPG > 240 mg/dL (13.3 mmol/L) or 
• 
HbA1c > 9% (for subjects with Baseline HbA1c < 8%) and HbA1c increase of more than 1% 
from Baseline (for subjects with Baseline HbA1c ≥ 8%) 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
18 
In case of FPL/HbA1c above the threshold values, 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 
 
A. Update: 
From baseline visit to Week 13 (including value at Week 13) of Randomized Treatment period: 
• 
Blood glucose > 270 mg/dL (15.0 mmol/L) 
From Week 13 to Post-treatment Follow-up (Week 4, 8 and 13 post end of treatment period): 
• 
Blood glucose > 240 mg/dL (13.3 mmol/L) or 
• 
HbA1c > 9% (for subjects with Baseline HbA1c < 8%) and HbA1c increase of more than 1% 
from Baseline (for subjects with Baseline HbA1c ≥ 8%) 
In case of blood glucose/HbA1c above the threshold values, the Investigator should ensure that no 
reasonable explanation exists for insufficient glucose control and in particular that: 
• 
Blood glucose was actually measured in the fasting condition 
B. Was: 
If none from the above-mentioned reason can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, rescue 
B. Update: 
If none from the above-mentioned reason can be found, or if appropriate action fails to decrease 
blood glucose/HbA1c under the threshold values, rescue 
Rationale:  
Monitoring for hyperglycemia did not include the post-treatment period. This change now 
incorporates that period. Fasting plasma glucose(FPG) has been updated to the more generic term 
“blood glucose” for this section to allow for measurements made with a glucometer.  
10. Follow-up Period Post-Treatment 
Section 3.4.3 Post-Treatment  
Was: 
Subjects are to return to the Study Center for follow-up visits.  These visits will take place at 4, 8 and 
13 weeks after the last dose. Refer to Schedule of Procedures in Appendix A. 
Update: 
Subjects are to return to the Study Center for follow-up visits.  These visits will take place at 4, 8 and 
13 weeks after the Treatment Period (last dose through one dosing interval post last dose). Refer 
to Schedule of Procedures in Appendix A. 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
19 
Section 6.1.3 Post-Treatment Period 
Was: 
Each subject will be followed for safety assessments for 13 weeks after the last dose of Study Drug.   
Update: 
Each subject will be followed for safety assessments for 13 weeks after the Treatment Period (last 
dose through one dosing interval post last dose).   
Section 8.8.1 Follow-up Visits for Early Termination from Treatment Period or from Post-Treatment 
Follow-up Period 
Was: 
Any subject who discontinues early from the treatment period or from post-treatment follow-up 
period should be followed as per the platelet monitoring rules shown 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 subjects are 
monitored for at least 13 weeks after discontinuing Study Drug. 
Update: 
Any subject who discontinues early from the treatment period or from post-treatment follow-up 
period should be followed as per the platelet monitoring rules shown in Section 8.6.3 for the first 6 
weeks after discontinuing Study Drug and then at 8  and 13 weeks post end of treatment period 
(as per visit schedule).   
Appendix A Schedule of Procedures and Appendix C PK Sampling Schedule 
The follow-up period after treatment period has been clarified in both tables and a footnote has been 
added to both appendices. 
 
Rationale: 
 
The follow-up period is meant to start after the last dose through one dosing interval post last dose. 
The prior language could be interpreted to not include the dosing interval post last dose.  
 
11. Section 9.4.1 Serious Adverse Events 
Was:  
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to Study Drug) 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 subject signs 
the informed consent form and stop at the end of the subject’s follow-up 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.   
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
20 
Update:  
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to Study Drug) 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 subject signs 
the informed consent form and stop at the end of the subject’s follow-up period.  An Initial Serious 
Adverse Event Form should be completed and a copy should be faxed to the Sponsor or designee.   
Rationale: 
To ensure that all pertinent information is reported, Akcea requires all clinical SAEs to be reported 
via two methods: 
1. Email: INCdrugsafety@incresearch.com (monitored 24/7) 
2. Fax: +1 877-464-7787  
Reporting SAEs only by Email and Fax ensures all information required for a valid and 
comprehensive case is received with proper documentation.  
12. Appendix E Mixed Meal Test 
A. Was: 
At Baseline, 3 months and end of study,… 
A. Update: 
At Qualification, 3 months and end of study,… 
B. Was: 
A cannula will be inserted into a forearm vein, and an overnight fasting venous blood sample will be 
taken… 
B. Update: 
A cannula will be inserted into a forearm vein, and an overnight fasting (minimum 10 hours) venous 
blood sample will be taken… 
Rationale: 
Procedure is to be done at Qualification and more detail is provided by specifying the minimum 
fasting time. 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
21 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial Lipodystrophy 
Study Phase 
2 
Indication 
Familial Partial Lipodystrophy (FPL) 
Primary Objective 
To assess the effect of ISIS 703802 on reduction in fasting triglycerides (TG). 
Secondary Objectives 
To evaluate the safety and tolerability of ISIS 703802  
To evaluate the effect of ISIS 703802 on changes from Baseline to end of 
treatment on: 
• 
Plasma glucose, serum insulin, serum C-peptide and free fatty acid 
(FFA) in responses to a mixed meal test (MMT) 
• 
Lipids, lipoproteins and lipid metabolism 
• 
Glycosylated hemoglobin (HbA1c) 
• 
Liver fat and body fat distribution 
• 
Quality of life and pain score 
 
To evaluate pharmacokinetics (PK) of ISIS 703802  
Study Design 
This is a single-center, open-label study. 
The study will comprise the following periods: 
Screening period: Up to 6 weeks (including an up to 4 week run-in diet 
period) 
Treatment Period: 26 weeks  
Post-treatment Follow-up Period: 13 weeks 
The primary safety and efficacy analysis time point is at Week 27. 
Number of Subjects 
Approximately 3 
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 the time of informed consent   
3. 
Clinical diagnosis of familial partial lipodystrophy plus diagnosis of type 
2 diabetes mellitus and hypertriglyceridemia.  
Diagnosis of lipodystrophy is based on deficiency of subcutaneous 
body fat in a partial fashion assessed by physical examination and low 
skinfold thickness in anterior thigh by caliper measurement: men (≤ 10 
mm) and women (≤ 22 mm), and at least 1 of the following:  
- Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPAR-γ, 
AKT2, CIDEC, PLIN1 genes)  
OR 
- Family history of FPL or family history of abnormal and similar fat 
distribution plus 1 Minor Criteria  
OR 
- 2 Minor Criteria (In the absence of FPL-associated genetic variant or 
family history) and BMI< 35 kg/m2  
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
22 
MINOR Criteria  
a. 
Requirement for high doses of insulin, e.g., requiring ≥ 200 
U/day, ≥ 2 U/kg/day, or currently taking U-500 insulin  
b. 
Presence of acanthosis nigricans on physical examination  
c. 
Evidence/history of polycystic ovary syndrome (PCOS) or 
PCOS-like symptoms (hirsutism, oligomenorrhea, and/or 
polycystic ovaries)  
d. 
History of pancreatitis associated with hypertriglyceridemia  
e. 
Evidence of non-alcoholic fatty liver disease  
- Hepatomegaly and/or elevated transaminases in the 
absence of a known cause of liver disease or radiographic 
evidence of hepatic steatosis (e.g., on ultrasound or CT)  
4. 
A diagnosis of diabetes mellitus, made at least 6 months prior to the 
Screening, and:  
• A HbA1c ≥ 7% to ≤ 12% at Screening,  
• On anti-diabetic therapy consisting of:  
a. 
Metformin ≥ 1500 mg/day, or  
b. 
If the dose of metformin is < 1500 mg/day, or metformin is 
not tolerated, then the patient should be on other oral anti-
diabetic drugs (OAD) or an injectable glucagon-like peptide-1 
(GLP-1) receptor agonist, or  
c. 
Insulin therapy alone or in combination with other anti-
diabetic drugs 
5. 
Hypertriglyceridemia as defined by Fasting TG levels ≥ 500 mg/dL (≥ 
5.7 mmol/L) at both Screening and Qualification visits. Patients with the 
clinical diagnosis of FPL and with Fasting TG levels ≥ 200 (≥ 2.26 
mmol/L) to < 500 mg/dL (≥ 5.7 mmol/L) at both Screening and 
Qualification Visits who meet the genetic or family history criteria for 
study inclusion may be further screened and enrolled in the study 
 
6. 
Presence of hepatosteatosis (fatty liver), as evidenced by a Screening 
MRI indicating a hepatic fat fraction (HFF) ≥ 6.4% 
 
7. 
Willing to maintain their customary physical activity level and to follow a 
diet moderate in carbohydrates and fats with a focus on complex 
carbohydrates and replacing saturated for unsaturated fats 
 
8. 
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 at least 13 weeks after 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
23 
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 at 
least 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. 
A diagnosis of generalized lipodystrophy 
2. 
A diagnosis of acquired partial lipodystrophy (APL) 
3. 
Acute pancreatitis within 4 weeks of 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 heart failure requiring a change in medication 
5. 
Major surgery within 3 months of Screening  
6. 
History of heart failure with New York Heart Association functional 
classification (NYHA) greater than Class II  
7. 
Uncontrolled hypertension (blood pressure [BP] > 160 mm Hg 
systolic and/or 100 mm Hg diastolic) 
8. 
Clinically-significant abnormalities in screening laboratory values that 
would render a subject unsuitable for inclusion, including the 
following: 
a. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event 
of a UPCR above this threshold, eligibility may be confirmed by a 
quantitative total urine protein measurement of ˂ 1 g/24-hr 
b. Estimated GFR ˂ 60 mL/min/1.73 m2 (as determined by the 
Chronic Kidney Disease-Epidemiological Collaboration (CKD-EPI) 
Equation  
c. Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 2x ULN 
d. Bilirubin > ULN, unless prior diagnosis and documentation of 
Gilbert’s syndrome in which case total bilirubin must be ≤ 3 mg/dL 
e. Alkaline phosphatase (ALP) > 1.5 X ULN 
f. Platelet count ˂ LLN 
9. 
Uncontrolled hyper- or hypothyroidism.  Subjects on dose stable 
replacement therapy for at least 3 months prior to Screening will be 
allowed 
10. History within 6 months of Screening of drug or alcohol abuse 
11. History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
24 
12. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Study Day 1 
13. Known history of or positive test for human immunodeficiency virus 
(HIV), hepatitis C or chronic hepatitis B 
14. 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 
15. Treatment with another investigational drug, biological agent, or device 
within 1-month of Screening, or 5 half-lives of investigational agent, 
whichever is longer 
16. Unwilling to comply with lifestyle requirements (see Section 6.3) 
17. Use of any of the following: 
a. 
Metreleptin within the last 3 months prior to Screening 
b. 
Antidiabetic, lipid lowering, or atypical antipsychotic medication, 
unless on a stable dose for at least 3 months prior to Screening.  
For lipid lowering medications (e.g., omega-3 fatty acids) dose, 
brand and regimen are expected to remain the same from Day 1 
throughout Week 13.  Patients not receiving these drugs within 
4 weeks prior to Screening are also eligible 
c. 
Insulin unless on a stable daily basal insulin dose regimen 
(± 20 %) for at least 4 weeks prior to dosing 
d. 
GLP-1 agonists within 4 weeks prior to dosing, if patient has a 
history of pancreatitis 
e. 
Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior 
to Screening 
f. 
Systemic corticosteroids or anabolic steroids within 6 weeks prior 
to Screening unless approved by the Sponsor Medical Monitor 
g. 
Antihypertensive medication unless on a stable dose for at least 
4 weeks prior to dosing 
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 throughout the study 
i. 
Oral anticoagulants unless on a stable dose for at least 4 weeks 
prior to dosing and regular clinical monitoring is performed 
j. 
Anti-obesity drugs [e.g., the combination of phentermine and 
extended-release topiramate (Qsymia), orlistat (Xenical), and 
lorcaserin (Belviq), phentermine, amphetamines, herbal 
preparations] within 12 weeks prior to Screening (except 
liraglutide [rDNA origin] injection (Saxenda) if on stable therapy 
for more than 6 weeks prior to Screening). 
k. 
Any other medication unless stable at least 4 weeks prior to 
dosing (occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion) 
18. Blood donation of 50 to 499 mL within 30 days of Screening or of          
> 499 mL within 60 days of Screening 
19. Have any other conditions, which, in the opinion of the Investigator or 
the Sponsor would make the patient unsuitable for inclusion, or could 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
25 
interfere with the patient participating in or completing the study 
Treatment Groups 
Single Group, open-label treatment with 20 mg of ISIS 703802 SC weekly 
Study Drug Dosage and 
Administration 
The Sponsor will provide ISIS 703802 in a single vial with a concentration of 
100 mg/mL 20 mg every week of ISIS 703802 (0.2 mL).  
The study dose of 20 mg (0.2 mL) of ISIS 703802 will be administered every 
week during the treatment period for a total of 26 weekly doses.  
All doses will be given by SC injection.  Self-administration will be allowed 
after appropriate training of subject and/or caregiver. 
Rationale for Dose and Schedule 
Selection 
A 20 mg weekly dose was selected as being the lowest dose that provided 
maximum TG lowering of approximately 60%, based on the TG lowering 
effect of ISIS 703802 observed in healthy volunteers with elevated TGs. 
Adjustment of Dose or Treatment 
Schedule 
Dose adjustments, including dose interruptions, and/or decreasing the dose 
and dose frequency may be allowed for safety or tolerability after consultation 
with the Sponsor Medical Monitor.   
Study Visit Schedule and 
Procedures 
Detailed information regarding the study procedures are outlined in Section 6, 
Appendices A and C. 
The study for an individual subject will generally consist of the following 
periods:  
• 
An up to 6-week Screening period, including a 4-week diet 
stabilization phase for subjects not already on a stable diet 
• 
A 26-week treatment period during which Study Drug will be 
administered weekly by SC injection 
• 
A 13-week post-treatment follow-up period 
During the Screening period, subject will be advised to maintain diet and 
exercise routines, and remain on a stable regimen of diabetes and lipid 
medications (if they are already taking any).  As part of the Screening period, 
subjects may have 4 weeks of diet run-in and final eligibility will be 
determined during qualification.  Subjects on stable diet known to the 
investigator and followed at the site may go from Screening to qualification 
without a 4-week diet run-in. At the qualification visit TGs will be measured. 
MRI and DEXA scan will be obtained during screening once all other eligibility 
criteria are met to assess liver fat content.   
Subjects meeting eligibility criteria at Screening and having a qualifying MRI, 
defined as having at least 6.4% liver fat assessed by MRI-PDFF (via central 
reviewer) will return to the clinic on Day 1.  In addition, TG will be measured 
at qualification and results of TG and MRI must be available prior to 
registration and administration of the first dose of study drug. 
Blood and urine samples will be collected regularly throughout the study for 
safety, efficacy, and PK analysis.  Appendix B shows a list of analytes 
required for the study and Appendix C details the PK sample schedules. 
The Mixed Meal Test (MMT) will be done at Baseline, at week 13 and at week 
27.  This test consists of having the subject consume a standardized meal in 
the evening and fast overnight for at least 8 hours.  The following morning, 
before the test, fasting plasma glucose, free fatty acids (FFA), C-peptide, 
insulin, serum ghrelin, GIP, GLP-1 and PYY as well as incretin hormones are 
measured.  The subject then consumes a liquid standard meal (such as 
Optifast®) and the same metabolic parameters are measured again over the 
course of 300 minutes at 10, 20, 30, 60, 90, 120, 150, 180, 240 and 300 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
26 
minutes.  In addition, a validated visual analogue scale (VAS) will be used to 
measure the subject’s perception of hunger. 
Safety and Tolerability 
Evaluations 
Safety and tolerability assessments include: AEs, vital signs and weight, 
physical examinations, clinical laboratory tests, ECGs, use of concomitant 
medications.   
Efficacy Evaluations 
Primary Endpoint:  
• 
The effect of ISIS 703802 on the percent change from Baseline in 
fasting triglyceride levels (TG) at week 27 
Secondary Endpoints: 
• 
Change from Baseline in AUC plasma glucose, serum insulin, serum 
C-peptide, free fatty acid, serum ghrelin, GIP, GLP-1, and PYY in 
response to a mixed meal test (MMT) 
• 
Change from Baseline in lipids and lipoproteins including high-
density lipoprotein cholesterol (HDL-C), low-density lipoprotein 
cholesterol (LDL-C), total cholesterol (TC), very low-density 
lipoprotein cholesterol (VLDL-C), non-HDL-C, apolipoprotein B 
(apoB), apolipoprotein B-48 (apoB-48), apolipoprotein B-100 (apoB-
100), apolipoprotein A-1 (apoA-1), apolipoprotein C-III (apoC-III: 
total, chylomicron, VLDL, LDL and HDL), Lipoprotein a [Lp(a)], free 
fatty acids (FFA), and glycerol levels, lipoprotein particle 
size/number 
• 
Change from Baseline in glycosylated hemoglobin (HbA1c) 
• 
Change from Baseline in homeostasis model assessment-estimated 
insulin resistance (HOMA-IR) 
• 
Change from Baseline in adiponectin and leptin 
• 
Change from Baseline in hepatic fat fraction (as assessed by 
magnetic resonance imaging [MRI]) 
• 
Changes from Baseline in body fat distribution for various areas in 
the body as measured by skinfold thickness and dual-energy X-ray 
absorptiometry (DEXA); visceral adipose tissue (VAT) and 
subcutaneous adipose tissue (SAT) as measured by MRI; body 
weight, waist circumference and waist/hip ratio 
• 
Changes from Baseline in quality of life and pain score 
Pharmacokinetic Evaluations 
Plasma samples will be taken from all patients for the measurement of 
ISIS 703802 trough levels throughout treatment and levels during the post-
treatment Follow-up period.  Plasma sample collection time points are 
detailed in Appendix A and Appendix C. 
Pharmacodynamic Evaluations 
Plasma angiopoietin-like 3 (ANGPTL3), HDL-C, LDL-C, TC, VLDL-C, non-
HDL-C, apoB, apoB-48, apoB-100, apoA-1, apoC-III, Lp(a), FFA, glycerol 
levels, lipoprotein particle size/number 
Statistical Considerations 
There is no statistical rationale for the selected sample size.   
Sponsor/Collaborator 
Akcea Therapeutics, Inc./ Ionis Pharmaceuticals, Inc. 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
27 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
TREATMENT PERIOD 
Weeks 1 to 26 
 
All Subjects will receive 20 mg of ISIS 
703802 administered weekly by SC injection 
Dosing, routine safety assessments, PK and 
PD/efficacy assessment at specified time 
points 
 
POST-TREATMENT 
EVALUATIONS                      
Week 4, 8 and 13 post-treatment 
3 clinical visits for safety, PK and PD 
assessments 
END-OF-STUDY 
PROCEDURES 
Early termination or 13 
weeks after end of 
Treatment Period 
EARLY 
TERMINATION 
(ET) 
Follow ET visit in 
Schedule of 
Procedures 
Patient strongly 
encouraged to visit 
clinic for post-
treatment 
SCREEN PERIOD Weeks -6 to 0 
Period may be reduced if the patient is following 
a stable low fat diet for a minimum of 4 weeks 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
28 
STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANA 
antinuclear antibody 
ANGPTL3 
Angiopoietin-like 3 
APL 
Acquired Partial Lipodystrophy 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
ASGPR 
Asialoglycoprotein Receptor 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the curve 
AUCt 
area under the plasma concentration-time curve from time zero to 
time t 
Bb 
complement factor Bb (activated complement split product) 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
centigrade 
C5a 
complement factor C5a (activated complement split product) 
Cmax 
maximum concentration 
CBC 
complete blood count 
CKD-EPI 
Chronic Kidney Disease Epidemiological Collaboration 
CL 
systemic clearance 
CMV 
Cytomegalovirus 
CRF 
case report form 
CRNMB 
Clinically-relevant Non-major Bleeding 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CS 
clinically significant 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTM 
Clinical Trial Manager 
DEXA 
dual-energy X-ray absorptiometry 
dL 
deciliter 
DLT 
dose-limiting toxicity 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
29 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
End of Treatment 
FFA 
Free Fatty Acid 
FHBL2 
Familial combined hypolipidemia 
FPG 
Fasting Plasma Glucose 
FPL 
Familial Partial Lipodystrophy 
FSH 
follicle-stimulating hormone 
g 
gram 
GalNAc 
N-acetyl galactosamine  
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GIP 
Gastric Inhibitory Polypeptide 
GLP-1 
Glucagon-like Peptide 1 
HAV 
hepatitis A virus 
Hb 
Hemoglobin 
HBA1c 
Glycosylated hemoglobin 
HBsAg 
hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
hepatitis C virus 
HDL 
High Density Lipoprotein 
HFF 
Hepatic Fat Fraction 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HOMA-IR 
Homeostasis Model Assessment-estimated Insulin Resistance 
HR 
heart rate 
hr, hrs 
hour(s) 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon-gamma 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1 beta 
IL-6 
interleukin-6 
INR 
international normalized ratio 
IRB 
Institutional Review Board 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
30 
ISIS 703802 
antisense inhibitor of ANGPTL3 
IV 
Intravenous(ly) 
kg 
kilogram 
L 
liter 
LDL-C 
Low Density Lipoprotein Cholesterol 
LPL 
Lipoprotein Lipase 
m2 
square meter 
MAD 
multiple ascending dose 
MB 
Major Bleeding 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
mg 
milligram 
min 
minute 
mL 
milliliter 
mm 
millimeter 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MMT 
Mixed Meal Test 
MTD 
maximum tolerated dose 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NEFA 
Non-esterified Fatty Acids 
NOAEL 
No Adverse Effect Level 
NCS 
not clinically significant 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
on study 
The insert [subject] or [patient] is ‘on study’ from signing of the 
informed consent until their last study visit 
OAD 
Oral Antidiabetic Drugs 
OTC 
Over the Counter 
PCOS 
Polycystic OvarySyndrome 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PLT 
Platelet  
pRBC 
packed red blood cells 
PT 
prothrombin time 
PYY 
Peptide Tyrosine Tyrosine 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
31 
RBC 
Red Blood Cells 
REMS 
Risk Evaluation ad Mitigation Strategy 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA 
strand in RNA/DNA hybrids 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAT 
Subcutaneous Adipose Tissue 
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
SMBG 
Self Monitored Blood Glucose 
Study Day 1 
defined as the first day Study Drug product is administered to the 
patient 
Study Drug 
ISIS 703802  
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TG 
Triglycerides 
Tmax 
time to maximal concentration 
TNF-α 
tumor necrosis factor-alpha 
T2DM 
Type 2 Diabetes 
ULN 
upper limit of normal 
UACR 
Urine albumin/creatinine ratio 
UPCR 
Urine Protein Creatinine Ratio 
VAT 
Visceral Adipose Tissue 
VLDL 
Very Low Density Lipoprotein 
WBC 
white blood cell 
WMA 
World Medical Association 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
32 
1. 
OBJECTIVES 
1.1 
Primary Objective 
The primary objective of this study is to assess the effect of ISIS 703802 on reduction in fasting 
triglycerides (TG). 
1.2 
Secondary Objective(s) 
The secondary objectives are: 
• 
To evaluate the safety and tolerability of ISIS 703802  
• 
To evaluate the effect of ISIS 703802 on changes from Baseline to end of treatment on: 
o Plasma glucose, serum insulin, serum C-peptide and free fatty acid (FFA) in responses to a 
mixed meal test (MMT) 
o Lipids, lipoproteins and lipid metabolism 
o Glycosylated hemoglobin (HbA1c) 
o Liver fat and body fat distribution 
o Quality of life and pain score 
• 
To evaluate pharmacokinetics (PK) of ISIS 703802. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Lipodystrophy syndromes are a group of rare metabolic diseases characterized by selective loss of 
adipose tissue that leads to ectopic fat deposition in liver and muscle and the development of insulin 
resistance, diabetes, dyslipidemia and fatty liver disease (Garg 2004; Chan and Oral 2010; Garg et al. 
2011; Shulman et al. 2014). 
These syndromes are categorized according to the distribution of fat loss into generalized or partial and 
according to the underlying etiology as inherited or acquired (Garg 2004; Chan and Oral 2010; Garg et al. 
2011). 
These syndromes constitute a significant medical unmet need as these patients are refractory to current 
therapies, mainly used to treat diabetes and elevated TG levels, in an attempt to reduce the risk of serious 
associated complications (coronary artery disease, diabetic nephropathy, cirrhosis and pancreatitis). 
As such, in February 2014, the FDA approved Myalept (metreleptin) as replacement therapy to treat the 
complications of leptin deficiency in addition to diet in patients with congenital or acquired generalized 
lipodystrophy.  The safety and effectiveness of Myalept was evaluated in 2 open-label studies conducted 
at the NIH, which included 72 patients (48 with generalized lipodystrophy and 24 with partial 
lipodystrophy [PL]) with diabetes, high TG, and elevated levels of fasting insulin.  The best results were 
achieved in patients with generalized lipodystrophy who had low leptin levels (mean [SD]: 1.3 [1.1] 
ng/mL), while patients with partial lipodystrophy who had a wider range of baseline leptin values (mean 
[SD]: 4.9 [3.1] ng/mL) had a more varied and attenuated response.  Because of the risks associated with 
the development of neutralizing antibodies and lymphoma, Myalept is available only through a risk 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
33 
evaluation and mitigation strategy (REMS) program, which requires prescriber and pharmacy certification 
and special documentation (Chan et al. 2011; Myalept PI). 
At the present time, the Sponsor does not intend to study the generalized forms for which a specific 
therapy exists (metreleptin) nor the acquired forms of the partial lipodystrophy disorders because of the 
heterogeneity of etiologies, some iatrogenic, and the high incidence of associated immune disorders in 
these populations.  Therefore, this study will focus only on patients with the congenital form of the partial 
lipodystrophy disorders and, among those, on the most severe subtype, patients with familial partial 
lipodystrophy, or FPL.  
Familial Partial Lipodystrophy (FPL) is an orphan disease for which no specific pharmacologic treatment 
currently exists.  FPL was described in the 1970s independently by Köbberling and Dunnigan (Dunnigan 
et al. 1974; Köbberling et al. 1975), and is the most common subtype of inherited PL (National 
Organization for Rare Disorders [NORD] 2012).  It has been estimated that FPL affects approximately 
0.2 in 10,000 people in the European Union, which is equivalent to a total of around 10,000 people 
(Committee for Orphan Medicinal Products 2012).  FPL encompasses several subtypes differentiated by 
the underlying genetic mutation (6 FPL subtypes and mutations in 5 genes have been identified).  FPL 
type 1, Köbberling variety has been reported in a handful of individuals and its molecular basis is 
unknown.  FPL type 2, Dunnigan variety is the most common form and the most well characterized 
disorder and is due to missense mutations in the A and C LMNA gene.  FPL type 3 has been reported in 
30 patients and is due to mutations in the PPARγ gene.  FPL type 4 has been reported in 5 patients and is 
due to mutations in the PLIN1 gene.  FPL type 5 has been reported in 4 members of a family who 
presented with insulin resistance and diabetes and is due to mutations in the AKT2 gene.  The last 
subtype, Autosomal Recessive FPL has been identified recently in 1 patient with homozygous mutations 
in CIDEC.  Some individuals with FPL do not have mutations in any of these genes, suggesting that 
additional, as yet unidentified genes can cause the disorder (Hegele et al. 2007; Garg et al. 2011; National 
Organization for Rare Disorders [NORD] 2012). 
The diagnosis of FPL is mainly clinical and needs to be considered in patients presenting with the triad of 
insulin resistance (with or without overt diabetes), significant dyslipidemia in the form of 
hypertriglyceridemia, and fatty liver (Huang-Doran et al. 2010).  Patients often present with diabetes and 
severe insulin resistance requiring high doses of insulin.  Other evidence of severe insulin resistance is 
provided by the presence of acanthosis nigricans and polycystic ovary syndrome (PCOS) (with symptoms 
like hyperandrogenism and oligomenorrhea).  Some patients develop severe hypertriglyceridemia 
resulting in episodes of pancreatitis.  In many patients, the TG levels remain persistently elevated despite 
fully optimized therapy or diet modifications.  Radiographic evidence of hepatic steatosis or 
steatohepatitis with hepatomegaly and/or elevated transaminases is common (Handelsman et al. 2013).  
Patients with the Dunnigan variety have a higher risk of coronary artery disease (Hegele 2001).  Although 
very rare, patients with a specific mutation in the LMNA gene are at an increased risk of cardiomyopathy 
and its associated complications, congestive heart failure and conduction defects. 
There is limited natural history data, mostly cross-sectional and derived from publication of baseline 
characteristics of patients entering a clinical trial (Diker-Cohen CE et al. 2015; Ajluni N et al. 2016; 
Akinci B et al. 2017; Ahmad Z et al. 2013; Bidault G. et al. 2013).  The evidence that FPL progresses 
over time comes from a prospective, open-label NIH study with ongoing enrollment since 2000 (N = 87).  
Data analyzed in 2014 showed that metabolic manifestations of the cohort of 32 partial lipodystrophy 
patients (including 25 FPL) were as severe as those of the cohort of generalized lipodystrophy (N = 55), 
which is recognized as a more severe form of lipodystrophy (Diker-Cohen CE et al. 2015).  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
34 
Patients with FPL have both a partial loss and maldistribution of adipose tissue leading to their distinct 
phenotype.  In many of these patients mutations in proteins involved in adipocyte differentiation, fatty 
acid uptake by adipocytes, triglyceride synthesis, or lipid droplet formation have been identified (Garg et 
al. 2011, Handelsman et al. 2013).  Due to this severe dysfunction of adipose tissue FPL patients have 
much lower TG storage capacity than patients with hypertriglyceridemia without FPL, highlighting the 
importance of TGs in the pathophysiology of FPL.  Plasma TG levels in FPL patients varied across 
studies from mean (25-75 percentile) 483 mg/dL (232, 856) (Diker-Cohen CE et al. 2015), median (25-75 
percentile) 342 mg/dL (279, 801) (Akinci B et al. 2017), mean 383 mg/dL (Bidault G et al. 2013), median 
389 mg/dL (155-3455) (Ahmad Z et al. 2013) and mean 1058 mg/dL (Ajluni N et al. 2016).  It is 
estimated that 1/4 to 1/5 of patients with FPL may have TG levels > 500 mg/dL. 
Due to inability of adipose tissue to accommodate excess TGs, TGs are deposited in higher amounts in 
organs other than adipose tissue that are less well adapted to excess lipid storage (“ectopic fat”) (Garg et 
al. 2011, Handelsman et al. 2013; Robbins et al. 2015; Nolis 2014; Huang-Doran et al. 2010). This 
ectopic fat accumulation has been found in and around many organs and is most clearly associated with 
metabolic abnormalities in the liver, pancreas and skeletal muscle contributing to severe insulin 
resistance, hepatic steatosis, diabetes and hypertriglyceridemia and increased risk of pancreatitis, non-
alcoholic steatohepatitis and cirrhosis (Robbins et al. 2015; Nolis 2014; Huang-Doran et al. 2010; Vatier 
et al. 2013; Sleigh A et al. 2012). 
Careful clinical assessment of fat distribution through visual and physical examination can confirm the 
diagnosis.  Patients with FPL have reduced subcutaneous fat in the limbs and truncal regions and may 
have excess subcutaneous fat deposition in neck, face and intra-abdominal regions.  Patients with the 
Dunnigan variety have normal body fat distribution in childhood and gradually lose subcutaneous fat 
from the extremities and trunk around the time of puberty.  In women, the loss of fat may be most striking 
in the buttocks and hips.  At the same time these patients accumulate fat on the face (“double chin”), neck 
and upper back (“Cushingoid appearance with buffalo hump”).  The extent of adipose tissue loss usually 
determines the severity of the metabolic abnormalities.  Patients display prominent muscularity and 
phlebomegaly (enlarged veins) in the extremities and complain of disproportionate hyperphagia.  The 
condition in females is more easily recognized than in men, and so is reported more often.  Patients may 
also have a family history of similar physical appearance and/or fat loss. 
Genetic testing, when available, is confirmatory. (Hegele et al. 2007; Huang-Doran et al. 2010; Garg et al. 
2011). 
Current treatment includes lifestyle modification such as reducing caloric intake and increasing energy 
expenditure via exercise.  Conventional therapies used to treat severe insulin resistance (metformin, 
thiazolidinediones, Glucagon-like peptide 1s [GLP-1], insulin), and/or high TGs (dietary fat restriction, 
fibrates, fish oils) are not very efficacious in these patients (Chan and Oral 2010). 
Familial Partial Lipodystrophy is an ultra-orphan indication for which there is a significant unmet medical 
need.  Diabetes, hepatic steatosis, and hypertriglyceridemia associated with this condition can lead to 
serious complications (Handelsman et al. 2013) such as: 
• 
Acute pancreatitis, especially when triglyceride levels are > 1,000 mg/dL 
• 
Accelerated microvascular complications from uncontrolled diabetes 
• 
Accelerated cardiovascular disease from lipid abnormalities and insulin resistance 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
35 
• 
Steatohepatitis that can progress to cirrhosis and an increased risk of hepatocellular carcinoma 
• 
Proteinuric nephropathies which can progress to end stage renal disease 
In patients with Generalized Lipodystrophy the metabolic complications are partially related to leptin 
deficiency, and can be ameliorated in part by leptin replacement.  However, leptin deficiency alone 
cannot explain the severity of metabolic disease in patients with PL who have variable leptin levels.   
By reducing ANGPTL3 and TG levels, ISIS 703802 may improve the metabolic profile of patients with 
FPL and reduce their risk of acute pancreatitis.  In addition, reductions in TG could improve hepatic 
steatosis and reduce cirrhosis risk. Furthermore, this mechanism may also improve insulin sensitivity in 
these patients and potentially lead to a reduction in the complications associated with diabetes.   
2.2 
Therapeutic Rationale 
In humans, loss of function mutations within the ANGPTL3 gene give rise to familial combined 
hypolipidemia (FHBL2), characterized by low plasma levels of triglycerides, total cholesterol, LDL-C, 
and HDL-C (Minicocci et al. 2012).  Homozygous individuals with complete ANGPTL3 deficiency 
showed the full combined hypolipidemic phenotype while individuals with more partial ANGPTL3 
deficiency showed a more attenuated phenotype.  Of note, FHBL2 homozygous were not affected by 
diabetes, showed lower plasma levels of insulin and lower degree of insulin resistance as estimated by 
HOMA-IR (Robciuc et al. 2013).   
ANGPTL3 protein is produced exclusively in liver, where its expression is downregulated by leptin and 
insulin (Inukai et al. 2004).  Hepatic specific knock-down of ANGPTL3 mRNA is associated with 
reduction in plasma triglycerides due to increased lipoprotein lipase activity as well as decreased hepatic 
VLDL triglyceride secretion.  Because ANGPTL3 is produced by the liver only, which does not express 
LPL, it is thought to function as an endocrine rather than paracrine factor with insulin sensitizing effects 
that go beyond the liver.  In fact, insulin sensitization has been shown in patients with ANGPTL3 gene 
mutations as well as in ANGPTL3-deficient mice, in which increased uptake of fatty acids into oxidative 
tissues such as muscle and brown adipose tissue led to decreased uptake of fatty acids and increased 
uptake of glucose in white adipose tissue (Wang et al. 2015).  Suppression of hepatic ANGPTL3 protein 
production in mice resulted in significant reductions in levels of triglycerides, LDL cholesterol, non-HDL 
cholesterol, and VLDL cholesterol and these favorable effects were associated with decreased liver 
triglyceride content, increases in insulin sensitivity, and a reduction in atherosclerosis progression 
(Graham et al. 2017).    
Treatment with ISIS 703802 would be expected to lower the hepatic expression of ANGPTL3 protein and 
result in lowering of the levels of triglyceride-rich lipoproteins and LDL-C, increased HDL-C, improved 
glycemic control and ameliorated insulin resistance in T2DM patients, leading to decreased liver fat 
content in NAFLD and ultimately, reduced overall risk of coronary artery disease.  
2.3 
ISIS 703802 
2.3.1 
Mechanism of Action 
ISIS 703802 is a second-generation ASO drug targeted to ANGPTL3 that has been covalently bonded to 
triantennary N-acetyl galactosamine (GalNAc), a high-affinity ligand for the hepatocyte-specific 
asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc conjugate.  This GalNAc-conjugate 
approach results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells and has 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
36 
increased ASO potency by approximately 10-fold in mice (Prakash et al. 2014).  The ASO portion of ISIS 
703802 is complementary to a region within the ANGPTL3 messenger ribonucleic acid (RNA) (mRNA) 
coding sequence, and binds to the mRNA via Watson and Crick base pairing.  The hybridization (binding) 
of ISIS 703802 to the cognate mRNA results in the Ribonuclease H1 (RNase H1)-mediated degradation 
of the ANGPTL3 mRNA, thus preventing production of the ANGPTL3 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, ISIS 703802 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are connected 
sequentially by phosphorothioate and phosphodiester linkages (mixed backbone design).  The mixed 
backbone design reduces the total number of phosphorothioate linkages in the MOE-modified regions, 
which reduces non-specific interactions with proteins and further enhances potency of GalNAc 
conjugated ASOs.  The nucleotide sequence of ISIS 703802 (Figure 1) is complementary to a 20-
nucleotide stretch within Exon 6 of the ANGPTL3 mRNA coding sequence at position 1169-1188 bp. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 
nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified ribonucleotides.  
These MOE-modified nucleotides confer (1) increased affinity for 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 ISIS 703802 employs this chimeric structure to enable use of the RNase H1 
mechanism for antisense activity.  This is because while the 2′-MOE modification confers increased 
stability and affinity, it does not support RNase H1 catalyzed cleavage of RNA hybridized to 2′-MOE-
modified nucleotides (McKay et al. 1999).  This is caused by conformational changes induced in the 
heteroduplex by 2′-alkoxy:RNA hybrids that are not recognized by RNase H enzymes (Inoue et al. 1987; 
Monia et al. 1993).  By limiting the 2′-MOE modification to nucleotides flanking the phosphorothioate 
oligodeoxynucleotide core, the beneficial attributes of the 2′-MOE chemistry are preserved while also 
retaining RNase H1 recognition.  The fourth region is comprised of a triantennary cluster of N-acetyl 
galactosamine (GalNAc) sugars which is linked to the 5ʹ end of ISIS 703802 via a phosphodiester 
linkage.  The GalNAc cluster is a high affinity ligand for the asialoglycoprotein receptor (ASGPR), a 
receptor expressed primarily on the surface of liver hepatocytes (Stockert 1995).  The GalNAc cluster 
enhances delivery of ISIS 703802 to liver hepatocytes over other cell types and enhances potency.  After 
internalization into cells, the GalNAc cluster is metabolized to release ‘free ASO’ inside the cell (Prakash 
et al. 2014). 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
37 
 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  
(MOE-Gapmer).  The sequence of ISIS 703802 is shown. 
2.3.3 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ANGPTL3 ASOs can be found in 
the Investigator’s Brochure.  A summary is included below. 
2.3.3.1 
Preclinical Pharmacology 
The pharmacology of ANGPTL3 ASOs has been examined in multiple in vitro cell lines where specific 
and dose-dependent reduction of ANGPTL3 mRNA and protein was clearly demonstrated, resulting in 
reductions in apoB secreted protein.  The pharmacology of ISIS 563580, an unconjugated 2′-MOE 
modified ASO that has the same base sequence as ISIS 703802, at doses higher than planned for ISIS 
703802. 
ISIS 563580 has been explored in human ANGPTL3 transgenic mice, wherein liver mRNA and plasma 
ANGPTL3 protein levels were reduced upon treatment with ISIS 563580. 
Reductions in murine ANGPTL3 mRNA and protein were routinely observed in all mouse models treated 
with a murine-specific ANGPTL3 ASO.  Pharmacology studies were done with Ldlr-/- mice fed a 
hypercholesterolemic diet known to develop elevated LDL-C, TG, and atherosclerosis, as well as features 
of metabolic syndrome (hyperglycemia and hyperinsulinemia) (Huszar et al. 2000; Schreyer et al. 2002; 
Tsuchiya et al. 2012).  Treatment of mice with a murine-specific ANGPTL3 ASO resulted in 
improvement in all of the aforementioned lipid and metabolic endpoints compared to controls.  In all 
mouse models tested, total plasma cholesterol, LDL-C, TG, and non-esterified fatty acids (NEFA) have 
been shown to be consistently reduced upon treatment with ANGPTL3 ASOs, while HDL-C is modestly 
decreased in wild type mice (- 22%), and either stable or increased in others.  While a clear mechanistic 
understanding of HDL-C reductions has not been elucidated, results from in vitro reverse cholesterol 
transport assays suggest that HDL function is maintained. 
Administration of ISIS 703802, a human specific, GalNAc conjugated, ANGPTL3 ASO, to human 
ANGPTL3 transgenic mice led to significant, dose-dependent reductions in hepatic ANGPTL3 mRNA.  In 
diet challenged mice, administration of ISIS 731875, a mouse-specific and GalNAc-modified ASO 
targeting ANGPTL3, led to dose-dependent reductions in both hepatic ANGPTL3 mRNA and plasma 
2′-MOE 
2′-MOE 
2′-Deoxy 
GalNAc = THA-GalNAc cluster 
2′-MOE = 2′-methoxylethyl RNA 
2′-Deoxy = DNA 
s = phosphorothioate linkage 
o = phosphodiester linkage 
(RNase H1 sensitive) 
GalNAc 
GsGoAoCoAo 
TsTsGsCsCsAsGsTsAsAs 
ToCoGsCsA 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
38 
ANGPTL3 with concomitant reductions in plasma TG and cholesterol.  Importantly, the potency and the 
lipid-lowering effects of the ANGPTL3 ASO were independent of diet. 
Finally, administration of a mouse-specific ANGPTL3 ASO to western diet fed Ldlr-/-, a mouse model of 
FH, also led to significant reductions in hepatic ANGPTL3 mRNA and plasma ANGPTL3 protein with 
concomitant reductions in plasma TG and LDL-C that were similar to what was observed in wild type 
western diet fed mice, indicating that the absence of Ldlr does not affect the ASOs potency or lipid-
lowering effects.  This suggests that administration of ANGPTL3 ASO administration is a promising 
target for clinical study in familial hypercholesterolemia patients. 
While formal pharmacology studies have not been conducted in the monkey with the human ANGPTL3 
ASO, hepatic mRNA expression has been shown to be reduced by more than 60% in cynomolgus 
monkeys, the same model used to conduct the toxicology evaluation. 
2.3.3.2 
Preclinical Toxicology 
General toxicology studies for ISIS 703802 consisted of sub-chronic (16-week) and chronic (26- or 39-
week) toxicity studies CD-1 in mice and cynomolgus monkeys.  Since ISIS 703802 is not fully 
complementary to the mouse ANGPTL3 transcript, treatment group receiving a mouse-specific inhibitor 
(ISIS 731875) was also included in the mouse study.  Please refer to the Investigator Brochure for a 
detailed description of the preclinical toxicology and pharmacokinetics with ISIS 703802. 
Pharmacokinetic data confirmed continuous and dose-dependent exposure to ISIS 703802.  An estimated 
liver and plasma terminal elimination half-life values of approximately 1 week and 3-4 weeks for 2 mg/kg 
and 35 mg/kg, respectively, were observed in monkeys.  The most noteworthy findings observed in mice 
and monkeys following ISIS 703802 treatment were, in general, non-specific class effects related to the 
uptake and accumulation of ASO and no toxicologically relevant findings were considered related to the 
pharmacologic inhibition of hepatic ANGPTL3 expression, either with the present series of studies or 
with the former development candidate targeting ANGPTL3.  There were no test-article related changes 
in PLT count in either mouse or monkey in both sub-chronic and chronic studies. 
The most noteworthy finding in the monkey was the kidney alteration (hypoalbuminemia and proteinuria) 
seen in one early-sacrifice animal from the 16-week study at 35 mg/kg/week, a dose equivalent to at least 
~190-fold of the 40 mg weekly clinical doses by plasma AUC.  Non-dose dependent increases in renal 
protein excretion (up to 2.2-fold in quantitative urine protein, protein/creatinine ratio or urine albumin) 
were also observed at 8 and/or 35 mg/kg/week (> ~30 to 190-fold of the 40 mg weekly clinical doses by 
plasma AUC) at the 16-week scheduled terminal necropsy.  However, Similar kidney alterations were not 
seen at the 6-week interim at any doses or in the 39-week chronic monkey study up to 12 mg/kg/week (> 
~200-fold of the 20 mg weekly clinical dose by plasma AUC). 
Additional findings related to ASO liver accumulation included increased alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) at ≥ 8 mg/kg/week in the 16- 
and 26-week mouse studies, and were correlated with individual hepatocyte necrosis (minimal to mild) in 
mouse liver.  Those changes were most prominent in the high dose groups (50 and 24 mg/kg/week for the 
16- and 26-week studies, respectively).  Conversely, no changes in liver enzymes were observed in 
monkeys from the 39-week toxicity study up to 12 mg/kg/week.  In the 16-week monkeys study, increase 
in ALT was only evident in one early-sacrifice animal at 35 mg/kg/week, and non-statistically significant 
increases in ALT (< 2-fold of the prestudy baseline) were also observed in the interim- and terminal-
sacrifice animals at ≥ 8 mg/kg/week but showed no microscopic correlates or dose-dependency. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
39 
Given the spectrum and severity of the test article-related clinicopathologic alterations present in 
monkeys at doses ≤ 12mg/kg/week (> ~100-fold of the 40 mg weekly clinical dose by plasma AUC) 
during the 39-week treatment phase, none would be regarded to represent an adverse effect (Dorato and 
Engelhardt 2005; Everds et al. 2013).  Considering the monkey to be the most relevant species, these data 
have characterized the safety profile and established appropriate therapeutic margins for the clinical 
evaluation of ISIS 703802 in humans. 
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 703802 can be found in the 
Investigator’s Brochure.  A summary is included below. 
The study drug, ISIS 703802, is being evaluated in Phase 1 in the clinical setting with single doses up to 
120 mg and multiple doses up to 60 mg (once per week for 6 weeks).  The parent drug ISIS 563580, an 
unconjugated 2′-MOE modified ASO that has the same base sequence as ISIS 703802, was also evaluated 
in a blinded, placebo-controlled Phase 1 study. 
An interim analysis of ISIS 703802 Phase 1 SAD/MAD Study (ISIS 703802-CS1) was performed in 44 
subjects administered single ascending (20, 40 and 80 mg) or multiple ascending doses (10, 20, 40 and 60 
mg/week for 6 weeks).  Twelve participants were randomly assigned to single-dose groups (9 to active-
agent dose groups and 3 to the placebo group) and 32 were randomly assigned to multiple-dose groups 
(24 to active-agent dose groups and 8 to the placebo group).  The main endpoints of the study were safety, 
tolerability, pharmacokinetics, pharmacodynamics and changes in lipids and lipoproteins.  After 6 weeks 
of treatment, persons in the multiple dose groups treated with ISIS 703802 had dose-dependent reductions 
in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from Baseline, P < 0.01 for all doses vs. 
placebo 1.6%) and in levels of triglycerides (reductions of 33.2 to 63.1% vs placebo 11.4%), LDL 
cholesterol (1.3 to 32.9% vs placebo 13.6%), very-low-density lipoprotein cholesterol (27.9 to 60.0% vs 
placebo 4.0%), non–high-density lipoprotein cholesterol (10.0 to 36.6% vs placebo 9.1%), apolipoprotein 
B (3.4 to 25.7% vs placebo 11.0%), and apolipoprotein C-III (18.9 to 58.8% vs placebo 3.1%).  There 
were no serious adverse events documented during the trial.  No protocol-defined injection-site reactions 
were reported.  Of those participants who received the multiple-dose regimen, three reported headache 
(one who received placebo and two who received ISIS 703802) and three reported dizziness (two who 
received placebo and one who received ISIS 703802).  There was no clinical evidence of prothrombotic 
effects, bleeding episodes, significant decreases in platelet count or thrombocytopenia, or significant 
changes in renal function.  One subject in the 60 mg weekly dose cohort had an approximately 5 x ULN 
increase of ALT, without increase in bilirubin and a second subject had an ALT of 88 U/L on Day 36 post 
treatment which returned to normal range by Day 50 and remained normal until the end of the study.  One 
subject in the 20 mg MAD group was lost to follow-up after 5 doses.  There were no other 
discontinuations during the treatment period (Graham et al. 2017 and data on file).  
The pharmacokinetics of ISIS 703802 evaluated in Study ISIS 703802-CS1 showed rapid absorption 
following SC administration, with median time to maximum plasma concentrations (Tmax) ranging from 1 
to 6 hours.  Similar Tmax values were observed at all dose levels.  After reaching Cmax, plasma 
concentrations of ISIS 703802 declined in a multi-phasic fashion with a rapid disposition phase, followed 
by a slower elimination phase with terminal elimination half-life of 3 to 5 weeks.  The peak (Cmax) and 
total exposure (AUC) after a single SC dose increased approximately dose proportionally from 20 to 
40 mg, and greater than dose proportionally from 40 to 80 mg, suggesting more efficient tissue uptake at 
lower doses.  After single and multiple SC doses in the range of 10 to 60 mg, the Cmax and AUC increased 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
40 
approximately dose proportionally.  No accumulation based on Cmax or AUC was observed after 6 weekly 
doses. 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD  
In a Phase 1 study, ISIS 563580-CS1, healthy volunteers received subcutaneous administration of 
ISIS 563580, an unconjugated 2′-MOE modified ASO that has the same base sequence as ISIS 703802, 
from 50 to 400 mg as a single dose, or 100 to 400 mg as multiple doses (8 doses in 36 days).  Overall, the 
safety findings from this study suggest that ISIS 563580 was not associated with any safety concerns.  
There were 383 adverse events (AE) reported in the ISIS 563580-treated subjects of which 363 (95%) 
were mild in severity.  For the multiple-dose subjects, the most common treatment-emergent adverse 
events were AEs at the injection site.  There was 1 serious adverse event (SAE) in the study of periorbital 
cellulitis which was considered a medically important event by the Investigator and was also considered 
unlikely related to Study Drug by the Investigator.  Together, the above suggest that ISIS 563580 was 
well-tolerated at the doses and regimen given, which exceed the dose levels and cumulative exposures to 
be tested in the current study.  There were no clinically-relevant changes in laboratory assessments and 
the heparin dose of 80 U/kg was well-tolerated in support of the post-heparin procedures.  ISIS 563580 
produced dose-dependent reductions in plasma ANGPTL3 (up to 93%; group means up to 84%), TG (up 
to 63%; group means up to 49%) and TC (up to 46%; group means up to 28%) at Day 36 (Brandt et al. 
2015). 
2.4 
Rationale for Dose and Schedule of Administration 
The Phase 1 program evaluated ISIS 703802 doses of 10 mg, 20 mg, 40 mg and 60 mg given weekly for 6 
weeks that were found to be generally well-tolerated and to induce clinically-relevant reductions in lipid 
biomarkers.  The dose proposed for the present study will provide the equivalent drug exposure of 20 mg 
weekly (80 mg monthly) and is predicted (based on modelling of PK/PD data obtained in Phase 1 study) 
to result in mean reductions from Baseline in TGs of approximately 63% at steady-state. 
Safety data from the available chronic mouse (26-week) and monkey (39-week) studies support 
once-weekly dosing for chronic administration.  The No Adverse Effect Level (NOAEL) for ISIS 703802 
in chronic monkey study was determined to be 12 mg/kg/wk.    
In healthy volunteers, 703802 achieved an equivalent reduction in ANGPTL3 plasma concentration to 
that of the unconjugated form, at approximately 1/10th of the unconjugated ASO (ISIS 563580) dose 
(Brandt et al. 2015).   
2.5 
Benefit-Risk Assessment 
The current study is designed to evaluate the safety and tolerance of ISIS 703802 in patients with FPL.  
The dose selected is expected to substantially reduce ANGPTL3 and result in a reduction of triglyceride 
levels, reduction of fat content of the liver and improvement of glycemic control.  We do not know if 
subjects participating in this study would necessarily benefit from the treatment.  However, the increased 
understanding of the effects of ISIS 703802 in this population may potentially result in new treatment 
options that would ultimately benefit FPL patients.  Due to the short duration of this trial any benefit 
observed is not expected to persist beyond the end of the study.  
2.5.2 
Risk Assessment 
The known potential risks to study participants associated with ISIS 703802 are elaborated on in the 
Guidance to Investigator section of the Investigator’s Brochure.  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
41 
• 
In preclinical mouse studies, there were increases in ALT and AST and were correlated with 
increased incidence and/or severity of necrosis of individual hepatocytes (minimal to mild in 
severity).  Those changes were most prominent in the high dose groups and showed no clear 
progression over time.  No increases in liver enzymes were observed in monkeys from the 39-
week toxicity study up to 12 mg/kg/week (~200-fold of the 20 mg/week clinical dose by plasma 
AUC).  In the 16-week monkey study, increase in ALT was only evident in 1 early-sacrifice 
animal at 35 mg/kg/week, no meaningful increase in ALT was observed in the schedule sacrificed 
animals. 
• 
In the Phase 1 study, there was no elevations in ALT at single dose cohorts up to 120 mg.  In 
multiple dose cohorts, two out of six subjects in the 60 mg weekly dose cohort had a    > 2 x ULN 
increase of ALT, without increase in bilirubin, which was considered a treatment related adverse 
event (AE) for one by Principal Investigator (PI).  There were no other observed clinically 
significant changes in ALT and liver function in Phase 1 human study (data on file).  However, to 
evaluate and mitigate the potential for liver enzyme abnormalities, regular liver chemistry 
monitoring and stopping rules are included in the study as specified in Sections 8.5 and 8.6.  
• 
Injection site adverse events, while not considered safety issues, may affect the ability of the 
subject to tolerate dosing.  Injection site adverse events are the most common side effects 
observed following SC administration of unconjugated 2′-MOE ASOs and are dose and 
concentration dependent.  Erythema is the most prevalent characteristic.  Generally, these events 
are mild and reversible, resolve spontaneously and do not worsen with time.  The histologic 
findings are consistent with a local inflammatory response.  Subjects should be informed of the 
possibility of occurrence of injection site adverse events.  Symptomatic interventions such as 
icing of the injection site or administration of NSAIDs prior to and/or after the SC dosing have 
been utilized. 
• 
Although no changes in platelet (PLT) counts have been observed in healthy volunteers, 
mouse or monkey in both sub-chronic and chronic studies with ISIS 703802, reductions in 
platelet counts to below the lower limit of normal have been observed after administration of 
other ASOs and some subjects have experienced severe thrombocytopenia following 
administration of unconjugated 2′-MOE ASOs.  To evaluate and mitigate the potential for a 
reduction in PLT count, monitoring and stopping rules are included in the study as specified in 
Sections 8.5 and 8.6 (Safety Monitoring Rules and Stopping Rules). 
• 
No significant changes in serum creatinine, electrolytes, BUN, or urinalysis were reported from 
the interim analysis of the ongoing Phase 1 study (data on file).  To evaluate and mitigate the 
potential for a reduction in renal function, since kidneys are an organ of high distribution for the 
studied ASO, monitoring and stopping rules are included in the study as specified in Sections 8.5 
and 8.6 (Safety Monitoring Rules and Stopping Rules). 
While the long term effects of reducing ANGPTL3 as a target with the study drug are not known at this 
time, there is evidence in literature in humans in whom ANGPTL3 is absent from plasma, due to 
homozygous or compound heterozygous ANGPTL3 mutations, present a pan-hypobetalipoproteinemia 
phenotype, with generalized and marked decreases (~50% to 70%) in all apoB-100 containing 
lipoproteins, including VLDL and LDL, as well as HDL.  This clinical phenotype has been termed 
familial combined hypolipidemia or FHBL2 (Romeo et al. 2009; Musunuru et al. 2010; Martin-Campos 
et al. 2012; Minicocci et al. 2012; Noto et al. 2012; Pisciotta et al. 2012; Wang et al. 2015).  Clinical 
studies in FHBL2 suggest a trend toward lower glucose and insulin levels and reported decrease in 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
42 
VLDL.  Remarkably, diabetes and cardiovascular disease are reportedly absent from those with 
homozygous FHBL2 and no adverse clinical phenotype has been reported to date. 
2.5.3 
Overall Assessment of Benefit: Risk 
ISIS 703802 has demonstrated the ability to reduce ANGPTL3, APOCIII, and TGs by greater than 60% 
and LDL-C by more than 30% in the Phase 1 study in healthy volunteers.  The objective of this study is to 
assess the effect of TG lowering in FPL patients.  This study will also investigate the potential of ISIS 
703802 in improving the insulin resistance and glucose profile, and decreasing liver and visceral fat 
content in these patients.  Although the subjects enrolled in this study will not derive long term benefits 
due to the short duration of the study, they may derive some short term benefit from improved metabolic 
health and dietary counselling.  The information obtained in the course of this study is critical to further 
development of ISIS 703802 for FPL patients.  
The protocol identifies that potential risks associated with ISIS 703802 treatment will be mitigated by 
routine monitoring.  Thus, exposure of subjects in this study is justified by the anticipated benefits that 
may be afforded to the wider population of patients by continued development of ISIS 703802. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 2 open-label multiple-dose study of approximately 3 subjects with FPL that will be treated 
with ISIS 703802.  Initially, 3 subject will be enrolled, but enrollment could be increased to 6 subjects, 
based on safety profile and efficacy observations.  
Subjects will be evaluated for study eligibility during Screening and Qualification, which takes place up 
to 6 weeks prior to Day 1 (the first day of Study Drug administration).  During the Screening period, 
subjects will be advised to maintain routine diet, and remain on a stable regimen of diabetes and lipid 
medications (if they are already taking any).  As part of the Screening period, following 4 weeks of diet 
run-in, subjects will have a qualification visit and final eligibility assessments will be performed.  
Subjects on stable diet known to the investigator and followed at the site may go from Screening to 
qualification without a 4-week diet run-in.  At the qualification visit TGs will be measured.  MRI and 
DEXA scan will be obtained during Screening once all other eligibility criteria are met to assess liver fat 
content.  MRI results must be available prior to registration and administration of the first dose of study 
drug. 
Subjects meeting eligibility criteria at qualification will return to the clinic on Day 1 for their first dose of 
ISIS 703802 by subcutaneous (SC) injection.  During the treatment period subjects will receive ISIS 
703802 (20 mg) administered every week for 26 weeks. 
Subjects will return regularly for outpatient visits throughout the treatment period according to the 
Schedule of Procedures (Appendix A).  The primary safety and efficacy analysis time point is at Week 
27.  
Subjects will then enter a 13 week Post-Treatment Follow-up Period and will return to the study center 
for outpatient evaluations according to the Schedule of Procedures (Appendix A). 
Blood and urine samples will be collected regularly throughout the study for safety, efficacy, and PK 
analysis.  Appendix B shows a list of analytes required for the study and Appendix C details the PK 
sample schedule. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
43 
3.2 
Number of Study Centers 
This study is planned to be conducted at a single center but will include additional centers if needed. 
3.3 
Number of Subjects 
Approximately 3 subjects will be treated in this study.  Initially, 3 subject will be enrolled, but enrollment 
could be increased to 6 subjects, based on safety profile and efficacy observations. 
3.4 
Overall Study Duration and Follow-up 
The length of subjects’ participation in the study may be up to 45 weeks.  This includes an up to 6-week 
screening period, that includes a 4-week diet stabilization / run-in period, a 2-week qualification period, a 
26-week treatment period, and a 13-week post-treatment evaluation period.  
Subjects may be required to attend additional visits for monitoring of adverse events or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Study Medical 
Monitor in consultation with the Investigator. 
3.4.1 
Screening/Qualification 
Subject eligibility for the study will be determined within 42 days/6 weeks prior to study entry.  Potential 
subjects will report to the Study Center for screening assessments at specified intervals within the 6-week 
screening period as detailed in the Schedule of Procedures in Appendix A.  As part of the screening 
period, subjects will have a 4-week diet stabilization/run-in period followed by a up to 2-week 
qualification period.  Subjects on stable diet known to the investigator and followed at the site may go 
from Screening to qualification without a 4-week diet run-in.  At the qualification visit TGs will be 
measured.  A baseline DEXA scan and MRI will be obtained to assess liver fat content once all other 
eligibility has been confirmed.  MRI results must be available prior to registration and administration of 
the first dose of study drug. 
3.4.2 
Treatment 
Eligible subjects will receive the first dose of study drug at the Study Center, at which time they will also 
be trained on self-administration of Study drug. Subsequent administrations of study drug may occur at 
home or in the Study Center.  
Eligible subjects will report to the Study Center for assessments at specified intervals throughout the 26 
week treatment period as detailed in the Schedule of Procedures in Appendix A.  
3.4.3 
Post-Treatment 
Subjects are to return to the Study Center for follow-up visits.  These visits will take place at 4, 8 and 13 
weeks after the Treatment Period (last dose through one dosing interval post last dose). Refer to Schedule 
of Procedures in Appendix A. 
4. 
SUBJECT ENROLLMENT 
4.1 
Screening 
Before subjects may be enrolled into the Study, the Sponsor or designee 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 subject information and/or recruitment material.  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
44 
Subjects must sign the consent form before any screening tests or assessments are performed.  At the time 
of consent, the subject will be considered screened into the Study and will be assigned a unique subject 
identification number before any study procedures, including screening procedures, are performed.  This 
number will be used to identify the subject throughout the trial and must be used on all study 
documentation related to that subject.  The patient identification number must remain constant throughout 
the entire trial.  Subject identification numbers, once assigned, will not be reused. 
4.2 
Registration 
Subjects will be registered after all screening assessments have been completed and after the Investigator 
has verified that they are eligible per criteria in Sections 5.1 and 5.2.  Once a subject is registered for the 
study, they are considered enrolled into the study.  No subject may begin treatment prior to assignment of 
a unique subject identification number nor confirmation of eligibility. 
4.3 
Replacement of Subjects 
Due to the small number of subjects participating in the study, subjects who withdraw from the study may 
be replaced by allowing a new subject to be screened and enrolled.  The subjects who withdrew for safety 
reasons will not be replaced.  
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria within 
42 days of treatment 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 the time of informed consent   
3. Clinical diagnosis of familial partial lipodystrophy plus diagnosis of type 2 diabetes mellitus and 
hypertriglyceridemia.  
Diagnosis of lipodystrophy is based on deficiency of subcutaneous body fat in a partial fashion 
assessed by physical examination and low skinfold thickness in anterior thigh by caliper 
measurement: men (≤ 10 mm) and women (≤ 22 mm), and at least 1 of the following:  
- Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPAR-γ, AKT2, CIDEC, PLIN1 
genes)  
OR 
- Family history of FPL or family history of abnormal and similar fat distribution plus 1 Minor 
Criteria  
OR 
- 2 Minor Criteria (In the absence of FPL-associated genetic variant or family history) and 
BMI< 35 kg/m2  
 
MINOR Criteria  
a. Requirement for high doses of insulin, e.g., requiring ≥ 200 U/day, ≥ 2 U/kg/day, or 
currently taking U-500 insulin  
b. Presence of acanthosis nigricans on physical examination  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
45 
c. Evidence/history of polycystic ovary syndrome (PCOS) or PCOS-like symptoms (hirsutism, 
oligomenorrhea, and/or polycystic ovaries)  
d. History of pancreatitis associated with hypertriglyceridemia  
e. Evidence of non-alcoholic fatty liver disease  
- Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver 
disease or radiographic evidence of hepatic steatosis (e.g., on ultrasound or CT)  
4. A diagnosis of diabetes mellitus, made at least 6 months prior to the Screening, and:  
• A HbA1c ≥ 7% to ≤ 12% at Screening,  
• On anti-diabetic therapy consisting of:  
a. Metformin ≥ 1500 mg/day, or  
b. If the dose of metformin is < 1500 mg/day, or metformin is not tolerated, then the patient 
should be on other oral anti-diabetic drugs (OAD) or an injectable glucagon-like peptide-1 
(GLP-1) receptor agonist, or  
c. Insulin therapy alone or in combination with other anti-diabetic drugs 
5. Hypertriglyceridemia as defined by Fasting TG levels ≥ 500 mg/dL (≥ 5.7 mmol/L) at both 
Screening and Qualification visits. Patients with the clinical diagnosis of FPL and with Fasting TG 
levels ≥ 200 (≥ 2.26 mmol/L) to < 500 mg/dL (≥ 5.7 mmol/L) at both Screening and Qualification 
Visits who meet the genetic or family history criteria for study inclusion may be further screened 
and enrolled in the study 
 
6. Presence of hepatosteatosis (fatty liver), as evidenced by a Screening MRI indicating a hepatic fat 
fraction (HFF) ≥ 6.4% 
 
7. Willing to maintain their customary physical activity level and to follow a diet moderate in 
carbohydrates and fats with a focus on complex carbohydrates and replacing saturated for 
unsaturated fats 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
46 
8. 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 at least 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 at least 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. A diagnosis of generalized lipodystrophy 
2. A diagnosis of acquired partial lipodystrophy (APL) 
3. Acute pancreatitis within 4 weeks of 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 heart failure requiring a change in medication 
5. Major surgery within 3 months of Screening  
6. History of heart failure with New York Heart Association functional classification (NYHA) greater 
than Class II  
7. Uncontrolled hypertension (blood pressure [BP] > 160 mm Hg systolic and/or 100 mm Hg diastolic) 
8. Clinically-significant abnormalities in screening laboratory values that would render a subject 
unsuitable for inclusion, including the following: 
a. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR above this 
threshold, eligibility may be confirmed by a quantitative total urine protein measurement of 
˂ 1 g/24-hr 
b. Estimated GFR ˂ 60 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation  
c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x ULN 
d. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
47 
e. Alkaline phosphatase (ALP) > 1.5 X ULN 
f. Platelet count ˂ LLN 
9. Uncontrolled hyper- or hypothyroidism.  Subjects on dose stable replacement therapy for at least 
3 months prior to Screening will be allowed 
10. History within 6 months of Screening of drug or alcohol abuse 
11. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in coagulation 
parameters at Screening 
12. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed 
prior to Study Day 1 
13. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B 
14. 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 
15. Treatment with another investigational drug, biological agent, or device within 1-month of 
Screening, or 5 half-lives of investigational agent, whichever is longer 
16. Unwilling to comply with lifestyle requirements (see Section 6.3) 
17. Use of any of the following: 
a. Metreleptin within the last 3 months prior to Screening 
b. Antidiabetic, lipid lowering, or atypical antipsychotic medication, unless on a stable dose for at 
least 3 months prior to Screening.  For lipid lowering medications (e.g., omega-3 fatty acids) 
dose, brand and regimen are expected to remain the same from Day 1 throughout Week 13.  
Patients not receiving these drugs within 4 weeks prior to Screening are also eligible 
c. Insulin unless on a stable daily basal insulin dose regimen (± 20 %) for at least 4 weeks prior to 
dosing 
d. GLP-1 agonists within 4 weeks prior to dosing, if patient has a history of pancreatitis 
e. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to Screening 
f. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Screening unless approved 
by the Sponsor Medical Monitor 
g. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to dosing 
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 throughout the study 
i. Oral anticoagulants unless on a stable dose for at least 4 weeks prior to dosing and regular 
clinical monitoring is performed 
j. Anti-obesity drugs [e.g., the combination of phentermine and extended-release topiramate 
(Qsymia), orlistat (Xenical), and lorcaserin (Belviq), phentermine, amphetamines, herbal 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
48 
preparations] within 12 weeks prior to Screening (except liraglutide [rDNA origin] injection 
(Saxenda) if on stable therapy for more than 6 weeks prior to Screening). 
k. Any other medication unless stable at least 4 weeks prior to dosing (occasional or intermittent 
use of over-the-counter medications will be allowed at Investigator’s discretion) 
18. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 60 days of 
Screening 
19. 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 
The study will consist of a Screening period, a Treatment period and a Post-treatment Follow-up period.  
These periods are described below.  
All required study procedures are outlined in Appendix A. 
6.1.1 
Screening/Qualification 
Written informed consent for the study will be obtained prior to the performance of any study-related 
procedures including screening procedures.  A 6-week period is provided for completing screening 
assessments and determining subject eligibility for the study.  During the screening period, subject will be 
advised to maintain diet and exercise routines, and remain on a stable regimen of diabetes and lipid 
medications (if they are already taking any).      
Subjects will undergo a medical history and physical examination including vital signs, 12-lead ECG, and 
have blood and urine samples taken for clinical laboratory testing.  Subjects will be screened for HIV, 
hepatitis B, and hepatitis C.  Safety labs may be re-tested for determination of subject eligibility after 
consultation with the Sponsor Medical Monitor. 
As part of the screening period, subjects not already on a stable diet will have 4 weeks of diet run-in, 
followed by a qualification visit, during which final eligibility assessments will be performed.  Subjects 
on stable diet known to the investigator and followed at the site may go from Screening to qualification 
without a 4-week diet run-in. At the qualification visit TGs will be measured. MRI and DEXA scan will 
be obtained during screening once all other eligibility criteria are met to assess liver fat content.  MRI 
results must be available prior to registration and administration of the first dose of study drug. 
6.1.2 
Treatment Period 
Subjects will be managed on an outpatient basis.  Safety and clinical laboratory evaluations as well as 
blood sampling for PK analysis will be performed periodically throughout the treatment period.  Any AEs 
and concomitant medications will be recorded.  
Collection and measurement of vital signs, physical examination results, ECGs, clinical laboratory 
parameters (Appendix B), ISIS 703802 plasma concentrations, immunogenicity, MRI, AEs and 
concomitant medication/procedure information will be performed according to the Schedule of 
Procedures in Appendix A. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
49 
6.1.3 
Post-Treatment Period 
Each subject will be followed for safety assessments for 13 weeks after the Treatment Period (last dose 
through one dosing interval post last dose).  During the post-treatment evaluation period, subjects will 
return to the Study Center for outpatient visits for safety and clinical laboratory evaluations.  A ± 3-day 
excursion from the scheduled visit date is permitted for this time period.  
6.2 
Study/Laboratory Assessments  
Laboratory analyte samples will be collected throughout the Study.  A list of these analytes is contained in 
Appendix B.   
Blood chemistry and urine samples (excluding 24-hour urine collection) should be taken after fasting for 
at least 10 hours.  During this time subjects can drink water and should ensure that they consume 
sufficient water to not become dehydrated.  
If tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or missing, a 
repeat blood or urine specimen should be re-drawn as soon as possible (ideally within 1 week).  
While on treatment hematology samples will be collected every 14 days.  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 samples are unreportable (e.g., due to 
hemolyzed or clumped blood samples), subject dosing cannot continue until another sample is repeated 
and determined not to have met a platelet stopping rule.  
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator will 
contact the subject to hold dosing until a new platelet count is obtained and reviewed.  
While on treatment blood samples for liver function testing will also be collected every 14 days and sent 
to the central laboratory for analysis for the first 3 months of the study treatment, and monthly thereafter 
during the Treatment Period per Section 8.5.1.   
While on treatment blood and urine samples for renal function testing will also be collected every 14 days 
and sent to the central laboratory for analysis per for the first 3 months of the study treatment, and 
monthly thereafter during the Treatment Period per Section 8.5.2.   
All lab samples are to be sent to the central laboratory by overnight courier and processed.  Lab Alerts 
issued as per protocol safety monitoring requirements or stopping rules will indicate the applicable 
protocol section to facilitate review and will be immediately and simultaneously sent by email to the 
Investigator, the Sponsor and the CRO Medical Monitors, the Sponsor Drug Safety Physician, and the 
Clinical Trial Manager (CTM), and should be received by them within 2 days from sample collection.  
Hematology results from the site’s local laboratories are received by the study center staff per the local 
laboratory’s standard reporting time, and should be entered as soon as possible into the eCRF to inform 
the Sponsor and CRO study monitoring teams.  
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the Investigator, or 
designee, to ensure that the count has not met the stopping rule and to determine whether the rate of 
decline is suggestive that the subject could be approaching the dose interruption rule of 75,000/mm3 as 
specified in Section 8.6.3.  Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or 
Grade 4) is considered an adverse event of special interest and must be reported in an expedited fashion to 
the Sponsor as per Section 9.4.1.  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
50 
All liver and renal function tests must also be reviewed promptly (within 48 hours of receipt) by the 
Investigator, or designee, to ensure that the result has not met the stopping rule.  Any event meeting renal 
stopping rules criteria described in Section 8.6.2 is considered an adverse event of special interest and 
must be reported in an expedited fashion to the Sponsor as per Section 9.4.1. 
All lab alerts received, including those related to platelet, liver, or renal function monitoring/stopping 
rules, are also reviewed promptly by the Sponsor and the CRO Medical Monitors who will agree on 
actions to be taken.  Within 24 hours of receiving an actionable lab alert the CRO Medical Monitor will 
communicate instructions to the Investigator and the study personnel by emailing them the Safety 
Surveillance Form that needs to be signed by the Investigator/study personnel and promptly returned to 
the Sponsor and CRO Medical Monitor.  In urgent cases, such as platelets results below 50,000/mm3, or 
liver or renal test results reaching a critical stopping rule the Investigator must also be contacted by 
phone.  
Further information on safety monitoring and actions to be taken by the Study Investigator in the event of 
reduced platelet count are provided in Sections 8.5.3 and 8.6.3. 
6.2.1 
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 (BP), pulse rate, respiratory rate and body 
temperature.  BP and pulse rate will be recorded after the subject has been in a sitting position for at least 
5 minutes.  BP should always be measured on the same arm (preferentially on the left arm).  Height will 
be measured at Screening. 
6.2.2 
DEXA Scan 
Dual-energy X-ray Absorptiometry (DEXA) scans will be conducted prior to administration of the first 
dose of Study Drug and repeated at Week 13 and 27 using standardized procedures and settings. 
6.2.3 
Electrocardiography  
Electrocardiography (ECG) will be conducted as indicated in the Schedule of Procedures (Appendix A) at 
Screening, Day 1 (prior to the first dose of Study Drug), and during the treatment period.  
ECGs will be conducted during the post-treatment follow-up period at scheduled visits. 
ECGs will be recorded after the subject has been resting in a supine position for at least 5 minutes.  ECGs 
will be performed in triplicate. 
6.2.4 
PK Sampling 
Blood samples for the determination of plasma ISIS 703802 concentrations will be collected prior to 
dosing on Day 1 and at various times throughout the treatment and post-treatment follow-up periods as 
noted in the tables in Appendix C. 
6.2.5 
Mixed Meal Test 
The Mixed Meal Test (MMT) (Appendix E) will be done at baseline, at week 13 and at week 27.  This 
test consists of having the subject consume a standardized meal in the evening and fast overnight for at 
least 8 hours.  The following morning, before the test, fasting plasma glucose, free fatty acids (FFA), C-
peptide, insulin, serum ghrelin, GIP, GLP-1 and PYY as well as incretin hormones are measured.  The 
subject then consumes a liquid standard meal (such as Optifast®) and the same metabolic parameters are 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
51 
measured again over the course of 300 minutes at 10, 20, 30, 60, 90, 120, 150, 180, 240 and 300 minutes. 
In addition, a validated visual analogue scale (VAS) will be used to measure the subject’s perception of 
hunger. 
6.2.6 
MRI 
An MRI to determine liver fat fraction will be done during Screening after all other eligibility criteria are 
met , and again at Week 13 and Week 27.  
6.3 
Restriction on the Lifestyle of Subjects 
6.3.1 
Contraception Requirements 
All male subjects and women of childbearing potential must refrain from sperm/egg donation and either 
be abstinent† or practice effective contraception from the time of signing the informed consent form until 
at least a period of 13 weeks after their last dose of study treatment.  
Male subjects engaged in sexual relations with a female of child-bearing potential must also encourage 
their female partner to use effective contraception from the time of signing the informed consent until a 
period of 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 subjects: 
• 
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 subjects with partners that are pregnant must use condoms as contraception to ensure that 
the fetus is not exposed to the Study Drug 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
52 
For female subjects and female partners of male subjects: 
• 
Using 2 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: 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. 
*Note: A female condom and a male condom should not be used together as friction between the 
two can result in either or both products failing. 
6.3.2 
Other Requirements 
All subjects will be required to fast for at least 10 hours before visits requiring fasted blood sampling.   
7. 
STUDY DRUG 
7.1 
ISIS 703802  
Study Drug (ISIS 703802) characteristics are listed in Table 1. 
Study Drug (ISIS 703802) will be provided as 0.8 mL deliverable volume in 2 mL stoppered and sealed 
glass vials as a sterile solution.   
The Study Drug is clear to slightly yellow in color, it is for single use, contains no preservatives and must 
be stored between 2 to 8 °Celsius and be protected from light. 
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 703802 
Strength 
100 mg/ mL  
Volume/Formulation 
0.8 mL/vial 
Route of 
Administration 
SC* 
* 
SC = subcutaneous 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with specific 
country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug (ISIS 703802) 
supplies provided by the Sponsor.  The subject must return all used and unused Study Drug to the Study 
Center for accountability. The Study Center must return all used and unused Study Drug to the Sponsor or 
designee.  All used syringes must be disposed of as per the site’s hazardous waste destruction policy. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
53 
8. 
TREATMENT OF SUBJECTS 
8.1 
Study Drug Administration 
Vials are for single use only.  Study staff will administer the first dose of Study Drug.  Doses will be 
administered by SC injection, patients or their caregivers may self-administer the study drug following 
the training given by the study center staff.   
Subjects will receive treatment weekly with weeks always defined relative to Study Day 1.  For example 
if a subject receives the first dose on a Monday, subsequent doses should be given on Mondays according 
to the respective dosing schedule, if possible.  If a subject misses an injection, or if dosing on the usual 
day is not possible, the subject can reschedule the injection provided that 2 doses are administered at least 
2 days apart.   
Every effort should be made to ensure the previous dose is given 7 days prior to a scheduled clinic visit. 
Volumes to be administered are shown in Table 2.  Please refer to the Study Drug Manual provided by the 
Sponsor or designee for more detailed instructions for Study Drug preparation and/or administration.  
Table 2 
Study Drug Dosing Information 
Volume to Administer* 
Total Dose* 
0.20 mL  
20 mg (open label) 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs.  
Subjects will continue their lipid-lowering therapy on a stable regimen from the signing of informed 
consent at Screening through the end of the post-treatment evaluation period. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures other than those outlined in the schedule of 
procedures. 
8.4 
Treatment Precautions 
No specific treatment precautions are required. 
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 the pre-dose test closest to 
Day 1 and Day 1. 
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.  
In case of discrepancy between the test results from 2 sources, safety-mandated action must be initiated 
based on the more critical (lower or higher, as relevant) of the 2 values.  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
54 
Confirmation Guidance:  At any time during the Study (Treatment or Post-Treatment Periods), the initial 
clinical laboratory results meeting the safety monitoring criteria presented below must be confirmed by 
performing measurements (ideally in the same laboratory that performed the initial measurement) on new 
specimens prior to administering the next dose of Study Drug.  All new specimen collections should take 
place as soon as possible (ideally within 3 days of the initial collection).   
Stopping Rule Guidance:  The Investigator may interrupt or permanently discontinue study treatment for 
any safety reason including clinically meaningful changes in clinical laboratory results.  
In the event of an initial clinical laboratory result that meets a stopping criterion, subjects must not be re-
dosed until a confirmatory test result has been reviewed by the Study Medical Monitor.  If any of the 
stopping criteria described below are met and are confirmed, the subject will be permanently discontinued 
from further treatment with Study Drug (ISIS 703802), evaluated fully as outlined below and in 
consultation with the Study Medical Monitor or appropriately qualified designee, and will be entered into 
the post-treatment evaluation portion of the study.  In general, subjects who do not meet the stopping 
rules based upon retest may continue dosing.  However, the Investigator and the Study Medical Monitor 
(or appropriately qualified designee) should confer as to whether additional close monitoring of the 
subject is appropriate.  
Additional Guidance:  If possible, a PK sample should be collected as soon as possible after a SAE has 
occurred (preferably within 2 weeks).  In addition, if a subject is asked to return to the clinic for 
additional evaluations due to an AE, then a PK sample should be taken at the time of the unscheduled 
visit. 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the FDA 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 and adopted to meet the requirements of this protocol and compound 
to ensure safety of the subjects.   
While on treatment, all subjects will have liver chemistry tests monitored every 2 weeks during the first 3-
months of the study treatment period, and monthly thereafter.  Upon completion of the study treatment 
period, liver chemistry tests should be monitored as per visit schedule in Appendix A.  
In the event of appearance of symptoms or signs of hepatic injury (jaundice, fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, abnormal bleeding or bruising, or eosinophilia  > 
ULN) liver enzymes and bilirubin should be tested as soon as possible.  Testing at a lab that is local to the 
subject is permissible for this purpose. 
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. 
Subjects with confirmed ALT or AST levels > 3 x ULN should have their liver chemistry tests (ALT, 
AST, ALP, international normalized ratio [INR] and total bilirubin) retested at least once-weekly until 
ALT and AST levels become ≤ 1.5 x ULN. 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
55 
Further Investigation into Liver Chemistry Elevations:  For subjects with confirmed ALT or AST levels > 
3 x 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 (hepatitis A virus [HAV] immunoglobulin M [IgM], hepatitis B 
surface antigen [HBsAg], hepatitis C virus [HCV] antibody, Cytomegalovirus [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 subject’s ALT and/or AST levels 
reach 5 x ULN. 
All routine liver function test results will be reviewed on an ongoing basis by the Medical Monitor.  
All lab alerts for abnormal liver function tests must be promptly (within 48 hours of receipt) reviewed by 
the Investigator and Medical Monitors. 
Lab alerts for abnormal liver chemistry tests will be issued for:  1) ALT or AST > 3 x ULN; 2) ALT or 
AST > 2 x baseline; 3) total bilirubin > ULN; 4) ALP > ULN.  These alert levels are set to anticipate the 
risk of a combined elevation of aminotransferases and bilirubin as per the FDA Guidance. 
8.5.2 
Safety Monitoring for Renal Function 
While on treatment all subjects will have renal function tests monitored every 2 weeks during the first 3 
months of the study treatment period, and monthly thereafter.  Upon completion of the study treatment 
period, urine renal biomarkers should be monitored as per visit schedule in Appendix A.  
In the event of appearance of symptoms or signs consistent with renal dysfunction such as hematuria, 
polyuria, anuria, flank pain, new-onset hypertension, nausea and/or anorexia, renal function should be 
tested as soon as possible.  Testing at a lab that is local to the subject is permissible for this purpose. 
While on treatment during the course of the study, urinary surveillance may include urinalysis to include 
urine albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and urinary red blood cells 
(RBCs), as well as serum creatinine and cystatin-C which will be monitored every 2 weeks during the 
first 3-months of the study treatment period, and monthly thereafter.  In addition, other biomarkers of 
acute renal injury may also be measured if a safety signal is seen that warrants further testing.  (Appendix 
B).  
The assessment of serum creatinine, cystatin-C, and urinalysis more frequently than per the Schedule of 
Procedures in Appendix A will be guided by consultation with the medical monitor.  Any decision taken 
by the Investigator to discontinue study medication will be made taking into account all available and 
relevant data.  In addition, the decision to discontinue Study Drug may also be based on lesser changes in 
these parameters observed in isolation or in association with other renal-related abnormalities.  Any 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
56 
decision taken to restart study medication will be made in consultation with the Study Medical Monitor 
taking into account all available and relevant data.  
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules. 
Lab alerts for abnormal renal tests will be issued for:  eGFR (by CKD-EPI formula) decrease from 
Baseline > 25%, urine albumin/creatinine ratio (UACR) > 250 mg/g, urine protein/creatinine ratio 
(UPCR) > 0.5 mg/mg, or an increase in serum creatinine from Baseline > 0.3 mg/dL). 
These alert levels are set to anticipate and prevent the risk of a medically significant change in renal 
function while receiving Study Drug. 
In the event of a confirmed laboratory result meeting one or more of the above criteria, the following 
supplemental renal tests should be immediately obtained:  
Serum creatinine, urine culture, 24-hour urine sample for creatinine clearance, urine albumin and 
urine protein, urine microscopy sample with inspection of sediment. 
The Investigator should also review the subject’s concomitant medications for potentially nephrotoxic 
agents, and, with the results of these evaluations, review any decision to continue or discontinue the 
subject in consultation with the Study Medical Monitor. 
8.5.3 
Safety Monitoring Rules for Platelet Count Results 
All subjects will have platelet counts monitored every 2 weeks for the duration of the study treatment 
period and must not receive Study Drug without an interpretable platelet count result in the prior 2 weeks.  
Upon completion of study drug dosing, platelets should be monitored every 2 weeks for the first 6 weeks 
and then at 8 and 13 weeks post last dose (as per visit schedule).  
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the Investigator or 
the designee to ensure that the count has not met the stopping rule and to determine whether the rate of 
decline is suggestive that the subject could be approaching the dose interruption rule of 75,000/mm3.   
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is considered an 
adverse event of special interest and should be reported in an expedited fashion to the Sponsor. In this 
case, the Investigator should refer the subject to a hematologist to provide diagnostic and therapeutic 
management. 
Lab alerts related to platelet monitoring/stopping rules are issued when:  1) platelet counts are < 140,000 
mm3; 2) when platelet count is ≥ 30% decreased from Baseline, or 3) when the hematology sample is 
unreportable.  All these lab alerts, are reviewed promptly by the Medical Monitor and instructions are 
communicated to the Investigator and the study personnel within 24 hours of receiving an actionable lab 
alert. 
Actions to be taken in the event of reduced platelet count are shown in Table 3. 
In the event of a platelet count ˂ 100,000/mm3 the laboratory tests outlined in Table 3, should be 
performed as soon as possible.  In addition to action taken as outlined in Table 3, in the event of a platelet 
count <100,000/mm3, tests outlined in Appendix F should be performed as soon as possible. Additional 
lab tests, if warranted, will be determined by the Sponsor Medical Monitor or designee in consultation 
with the Investigator.  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
57 
8.5.4 
Safety Monitoring for Bleeding Events 
Subjects will be evaluated for occurrence of bleeding events continuously after the start of Study Drug 
treatment (Day 1) up to the end of the follow-up period for all cohorts.  All bleeding events are considered 
adverse events and reported on adverse event case report form.   
Bleeding events that are either major or clinically-relevant non-major bleeding (as defined below) will 
need to be monitored and treated immediately. Subjects with a suspected bleeding event will undergo 
additional testing if deemed appropriate by the treating physician and an (S)AE case report form will be 
completed. In addition, if bleeding is considered significant, hemoglobin (Hb), hematocrit (HCT), aPTT, 
PT, INR, and platelet count are to be obtained.  In addition, approximately 2 mL of K2EDTA 
anticoagulated blood will be collected and resulting plasma must be stored allowing for a centralized 
assessment of ISIS 703802 concentrations.  
In addition, if a minor bleeding event occurs, the Investigator should notify the Sponsor Medical Monitor 
(or designee) and additional testing of coagulation parameters (aPTT, prothrombin time [PT], INR), 
platelet count, and platelet volume may be performed. 
Definitions:  
Major bleeding (MB) is defined as one of the following (Büller et al. 2007):  
1. Fatal bleeding  
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
retroperitoneal, intraarticular if in a major joint, or pericardial, or intramuscular with 
compartment syndrome  
3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed red blood cells or whole 
blood or a fall in hemoglobin of 20 g/L (1.24 mmol/L) or more within 24 hours  
Clinically-relevant non-major bleeding (CRNMB) is defined as overt bleeding not meeting the criteria for 
major bleeding but that resulted, for example, in medical examination, intervention, or had clinical 
consequences for a subject (Büller et al. 2007).  
 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-relevant, 
non-major bleeding events (defined above), for example excess bruising, petechiae, gingival bleeding on 
brushing teeth.  
8.5.5 
Safety Monitoring for Constitutional Symptoms 
Subjects will be instructed to promptly report any signs or symptoms of fever, constitutional symptoms, 
rash, arthralgia or joint swelling that may arise during the study and the Investigator should closely 
evaluate all potential causes, including concomitant illness.  Subjects who experience persistent 
symptoms should be discussed with the Sponsor Medical Monitor or designee to determine whether 
additional monitoring or laboratory tests are required.   
8.5.6 
Safety Monitoring for Hypoglycemia 
Subjects will be instructed to monitor and manage hypoglycemic episodes. Subjects will be provided with 
glucometer and asked to record Self Monitored Blood Glucose (SMBG) levels and report back alert 
values to the site.  Subjects will be instructed to promptly report symptoms of hypoglycemia: headache, 
heart pounding, confusion, disorientation, numbness or tingling, pale skin, shakiness or tremulousness, 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
58 
increased appetite, anxiousness or nervousness, lightheadedness or dizziness, sweating and weakness.  If 
subjects 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.  If a 
subject presents with symptoms of hypoglycemia, the Investigator will need to take immediate action to 
confirm the subject’s glucose level and treat the subject accordingly.  Severe hypoglycemia will be 
qualified as a SAE only if it fulfills SAE criteria. 
Classification of Hypoglycemia 
The alert value for hypoglycemia is ≤ 70 mg/dL (≤ 3.9 mmol/L) blood glucose concentration. 
Severe Hypoglycemia 
Requires assistance of another person to actively administer carbohydrates, glucagon, or take other 
corrective actions.  Glucose concentrations may not be available during an event. Neurological recovery 
following glucose levels returning to normal considered sufficient evidence that event was induced by 
low glucose concentration. 
Documented Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms accompanied by measured blood glucose ≤ 70 mg/dL (≤ 3.9 mmol/L).  
Asymptomatic Hypoglycemia  
Not accompanied by typical hypoglycemia symptoms but with measured blood glucose≤ 70 mg/dL (≤ 3.9 
mmol/L). 
Probable Symptomatic Hypoglycemia 
Typical hypoglycemia symptoms not accompanied by blood glucose determination but likely caused by 
blood glucose ≤ 70 mg/dL (≤ 3.9 mmol/L). 
A documented severe hypoglycemic event is defined as one in which the subject requires assistance of 
another person to obtain treatment for the event and has a blood 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 subjects at 
risk for injury to themselves or others. 
8.5.7 
Safety Monitoring for Documented Hyperglycemia 
Subjects will be asked to self-monitor their glucose at least once a week and reviewed by Investigator at 
each Study Center visit.  If the value exceeds the specific glycemic limit specified below, the subject will 
be instructed to check again during the 2 following days.  If all values in 3 consecutive days exceed the 
specific limit, the subject should contact the Investigator and a central laboratory FPG measurement will 
be performed).  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
59 
The threshold values are defined as follows, depending on study period: 
From baseline visit to Week 13 (including value at Week 13) of Randomized Treatment period: 
• 
Blood glucose > 270 mg/dL (15.0 mmol/L) 
From Week 13 to Post-treatment Follow-up (Week 4, 8 and 13 post end of treatment period): 
• 
Blood glucose > 240 mg/dL (13.3 mmol/L) or 
• 
HbA1c > 9% (for subjects with Baseline HbA1c < 8%) and HbA1c increase of more than 1% 
from Baseline (for subjects with Baseline HbA1c ≥ 8%) 
In case of blood glucose/HbA1c above the threshold values, the Investigator should ensure that no 
reasonable explanation exists for insufficient glucose control and in particular that: 
• 
Blood glucose was actually measured in the fasting condition 
• 
Absence of intercurrent disease which may jeopardize glycemic control.  In case of an emergency 
such as unplanned hospitalization (e.g., surgery, infection), the Investigator can take appropriate 
measures for glycemic control.  If the measure does not exceed 7 days, then it will not be 
considered a rescue.  If the measure lasts beyond 7 days then it will be treated as a rescue 
• 
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 
undertake appropriate action, i.e.: 
• 
Investigation and treatment of intercurrent disease (to be reported in AE/concomitant medication 
parts of the eCRF) 
• 
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 
• 
Schedule a FPG/HbA1c assessment at the next visit 
If none from the above-mentioned reason can be found, or if appropriate action fails to decrease blood 
glucose/HbA1c under the threshold values, rescue medication may be introduced at the Investigator 
discretion and according to local guidelines. 
All assessments for primary and secondary efficacy and safety parameters planned in final primary 
endpoint assessment visit should be performed before adding the rescue medication if possible.  Then the 
subject continues the study treatment and stays in the study in order to collect safety information.  The 
planned visits and assessments should occur until the last scheduled visit.  (See more details in Appendix 
A). 
Note: After Study Drug discontinuation any treatments are permitted, as deemed necessary by the 
Investigator. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
60 
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 confirmed laboratory results meeting any of the following criteria, dosing of a patient with 
Study Drug will be stopped permanently: 
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. 
Dose adjustments, including dose interruptions, and/or decreasing the dose or dose frequency will be 
allowed for safety.  Any proposed adjustments to treatment schedule must be discussed with, and 
approved by, the Study Medical monitor prior to initiation.  
8.6.2 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for Renal 
Function Test Results 
In the event of an eGFR (by CKD-EPI formula) meeting any of the following criteria, or any change in 
renal biomarkers deemed by the nephrologist to require further evaluation, a serum creatinine and 24-hour 
urine sample for creatinine clearance and protein should be obtained: 
1. eGFR (CKD-EPI) decrease of > 40% from Baseline 
2. eGFR (CKD-EPI) value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (ISIS 703802) will be stopped permanently if 24-hour urine testing 
confirms any of the following values in the absence of an alternative explanation: 
1. Urine protein is > 1.0 g 
2. Creatinine clearance decrease of > 40% from Baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, the follow-up schedule and frequency of 
renal function monitoring after the initial event will be determined by the Study Medical Monitor in 
consultation with the Investigator.  The Investigator should consider consulting a local nephrologist for 
any change of renal function that presents a concern.  If a renal biopsy is performed, a sample specimen 
should be made available for examination by an independent renal pathologist who has been engaged by 
the Sponsor to review such specimens.  
Dose adjustments, including dose interruptions, and/or decreasing the dose or dose frequency will be 
allowed for safety.  Any proposed adjustments to treatment schedule must be discussed with, and 
approved by, the Study Medical monitor prior to initiation.  


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
61 
8.6.3 
Stopping Rule 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 any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 that 
occurs while the subject is already on reduced dose, dosing of the subject with Study Drug will be 
stopped permanently (Table 3).  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 subjects 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 ˂ 75,000/mm3 and > 50,000/mm3, dosing of a subject with Study Drug 
should be suspended temporarily until the platelet count has recovered to > 100,000/mm3.  If dosing is 
continued, it must be at a reduced dose as shown in Table 3.  The suitability of the subject 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 subject’s platelet count, whether any bleeding 
events were experienced by the subject, and the speed of recovery of platelet count after interruption of 
dosing. 
If, after reintroduction of Study Drug, the platelet count again falls below 75,000/mm3, then dosing of the 
subject with Study Drug will be stopped permanently.  
Once a subject commences weekly monitoring, this frequency of monitoring should continue until the 
platelet count returns to the normal range (≥140,000/mm3) for 2 successive values. 
Any unreportable platelet count result must be rechecked and determined not to have met a stopping rule 
before dosing can continue. 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
62 
Table 3 
Actions in Subjects with Low Platelet Count  
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 14 days (+/- 2 days) 
>100K to <140K/mm3 
No action 
Closer observation 
Monitor every week * 
>75K to <100K/mm3 
Permanently reduce as follows: 
Reduce to 10 mg every week 
Closer observation  
Monitor every week* 
>50K to <75K/mm3 
Pause dosing 
When platelet count returns to 
≥ 100K/mm3 restart dosing as follows 
only if approved by Sponsor Medical 
Monitor: 
Reduce to 10 mg every week 
or 
Permanently discontinue Study Drug if 
it occurs while on already reduced 
dose  
Closer observation 
Monitor every 2-3 days until 2 successive 
values show improvement 
Consider discontinuation of antiplatelet 
agents/non-steroidal anti-inflammatory 
drug (NSAIDS)/ anticoagulant medication 
>25K to <50K/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 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant medication 
while platelet count ˂ 50K/mm3 if possible. 
Refer to hematologist to provide 
diagnostic and therapeutic management. 
˂ 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 t 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant medication 
while platelet count ˂ 50K/mm3 if possible 
Refer to hematologist to provide 
diagnostic and therapeutic management. 
* 
Once a subject commences weekly monitoring this frequency of monitoring should continue until the platelet 
count returns to the normal range (≥ 140,000/mm3) for 2 successive values.   
** 
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). 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
63 
8.7 
Adjustment of Dose and/or Treatment Schedule 
Dose frequency 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 will be allowed for 
safety or tolerability in consultation with the Sponsor Medical Monitor.   
Subjects may have their dose interrupted in response to AEs in consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Drug/Treatment 
A subject must permanently discontinue study treatment for any of the following: 
• 
The subject becomes pregnant.  Report the pregnancy according to instructions in Section 9.5.4 
• 
The subject withdraws consent 
• 
The subject experiences an adverse event (AE) that necessitates permanent discontinuation of 
Study Drug 
• 
The subject develops laboratory test abnormalities that meet any of the stopping rules listed in 
Sections 8.6.1 to 8.6.3 
• 
When a platelet count of less than 50,000/mm3, or a platelet count less than 75,000/mm3 while the 
patient is on a reduced dose. 
The reason for discontinuation of Study Drug Treatment must be recorded in the electronic Case Report 
Form (eCRF) and source documentation.  
For subjects who discontinue treatment early every effort should be made to complete the early 
termination study procedures and observations at the time of withdrawal (see Appendix A).  Subjects 
should then be entered into the post-treatment evaluation period.   
If a subject discontinues treatment after only 1 dose, then the post-treatment evaluation procedures should 
be followed.  
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from Post-Treatment 
Follow-up Period 
Any subject who discontinues early from the treatment period or from post-treatment follow-up period 
should be followed as per the platelet monitoring rules shown in, Section 8.6.3 for the first 6 weeks after 
discontinuing Study Drug and then at 8 and 13 weeks post end of treatment period (as per visit schedule).  
If the subject declines or is unable to participate in the above, the early termination visit procedures 
should be performed at the time of withdrawal, at a minimum, and ideally within 2 weeks from the last 
dose of Study Drug.  In addition, the investigator should clarify what type of follow-up the subject is 
agreeable to: in person, by phone/mail, through family/friends, in correspondence/communication with 
other physicians, and/or from review of the medical records.  Wherever possible these subjects should 
continue to be followed up via the agreed means to collect information on adverse events, concomitant 
medications and survival status.  At the very least, the patient’s status at the end of the protocol defined 
study period should be ascertained and documented. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
64 
8.9 
Withdrawal of Subjects from the Study 
Subjects must be withdrawn from the Study for any of the following: 
• 
Withdrawal of consent 
• 
The subject is unwilling or unable to comply with the protocol 
• 
The subject meets any of the Exclusion Criteria (see Section 5.2) after enrolling in the study that 
in the opinion of the Investigator represents a safety risk to the subject 
Other reasons for withdrawal of subjects 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 
eCRF.  
Any subject who withdraws consent to participate in the Study will be removed from further treatment 
and study observation immediately upon the date of request.  These subjects should be encouraged to 
complete the early termination study procedures and observations at the time of withdrawal (Appendix 
A). For subjects 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 
Appendix A).  The Investigator should clarify what type of follow-up the subject is agreeable to: in 
person, by phone/mail, through family/friends, in correspondence/communication with other physicians, 
and/or from review of the medical records.  Wherever possible these subjects should continue to be 
followed up via the agreed means to collect information on adverse events, concomitant medications and 
survival status.  At the very least, the patient’s status at the end of the protocol defined study period 
should be ascertained and documented. 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’s eCRF.  
Adverse events related to administration of these therapies or procedures must also be documented on the 
appropriate eCRF. 
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 Screening and the end 
of the post-treatment evaluation period. All concomitant medications/treatments and significant non-drug 
therapies (including supplements and assistive devices) received by a subject, including changes in the 
subject’s current medications, must be recorded in the subject’s source documents and CRF.  Subjects 
taking over the counter (OTC) omega-3 fatty acids should make every effort to remain on the same brand 
throughout the study. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
65 
Allowed Concomitant Therapy 
Ibuprofen may be used for symptomatic pain relief.  Any other therapy for pain (including OTC 
medications such as acetaminophen) should be approved by the Sponsor Medical Monitor or designee.  
Disallowed Concomitant Therapy 
The use of prescription and OTC medications including nonsteroidal anti-inflammatory drugs (with the 
exception of occasional ibuprofen) is prohibited during this study unless the occurrence of an AE requires 
a drug therapy.  In cases when there is no AE, the Investigator must consult the Sponsor Medical Monitor 
to decide on subject continuation or withdrawal from the study.  
The medications and therapy identified in exclusion criteria, Section 5.2 are also disallowed concomitant 
medications and are prohibited during the course of study, unless there is a safety concern.  In those cases 
the Medical Monitor needs to be notified and rationale provided by the Investigator. 
Concomitant therapy with oral corticosteroids used as replacement therapy for pituitary adrenal disease as 
well as inhaled steroid therapy (e.g., Pulmicort®), or intra-articular, or topical may be acceptable; 
however, the subject must be on a stable regimen for at least 4 weeks prior to Screening.  All exceptions 
should be discussed with the Sponsor Medical Monitor. 
Subject 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 Screening and 
the end of the post-treatment evaluation period. 
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 study medication.  
Subjects that are self-administering study medication 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 or designee in accordance 
with the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor or designee 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. In addition to the Investigator’s assessment of relatedness, the 
Sponsor or designee will evaluate the available information and perform an independent assessment of 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
66 
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. For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population. 
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 AE caused by the Study Drug. A suspected adverse reaction is any AE for 
which there is a reasonable possibility that the 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 subject 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 a congenital anomaly or birth defect in the offspring of the subject (whether the subject 
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 subject 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. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
67 
9.3.3.1 
Adverse Events of Special Interest 
For the purpose of this study severe reductions in platelet count < 50,000 mm3 are considered as an AE of 
special interest and should be subject to expediting reporting to the Sponsor following the same 
requirements as for SAE reporting (Section 9.4.1). 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject 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 subject safety, and in order to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to Study Drug) 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 subject signs the 
informed consent form and stop at the end of the subject’s follow-up period. An Initial Serious Adverse 
Event Form should be completed and a copy should be faxed to the Sponsor or designee.   
The contact information for reporting SAEs is as follows: 
Attention:INC Research, LLC 
Email:INCDrugSafety@INCResearch.com 
Fax:1-877-464-7787 
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 subject’s last protocol-specified follow-up visit will be evaluated by the 
Investigator and Sponsor.  If the Investigator and Sponsor agree the subject’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 subject signs the informed consent form and will 
stop at the end of the subject’s follow-up period.  The Investigator will monitor each subject 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: 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
68 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 703802) is characterized by 1 of the following: 
• 
Related:  There is clear evidence that the event is related to the use of Study Drug, e.g., 
confirmation by positive re-challenge test 
• 
Possible:  The event cannot be explained by the subject’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event and 
Study Drug (ISIS 703802) 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 Study 
Drug (ISIS 703802) 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 subject’s underlying medical condition, 
concomitant therapy, or other causes, and therefore, the Investigator believes no relationship 
exists between the event and Study Drug 
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 subject and does not affect the subject’s usual daily 
activities 
• 
Moderate:  The event causes the subject more discomfort and interrupts the subject’s usual daily 
activities 
• 
Severe:  The event is incapacitating and causes considerable interference with the subject’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 Study Drug 
Action taken with Study Drug (ISIS 703802) due to the event is characterized by 1 of the following: 
 
• 
None:  No changes were made to Study Drug (ISIS 703802) administration and dose 
• 
Permanently Discontinued:  Study drug 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 
• 
Temporarily Interrupted, Restarted Reduced Dose:  Dosing was temporarily interrupted or 
delayed due to the AE and restarted at the next lower dose 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
69 
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 eCRF, 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:  Subject terminates from the trial and the AE continues: 
 
• 
Recovered:  Subject 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 an SAE, then the event’s outcome is characterized by 1 of the following: Ongoing:  SAE 
continuing: 
 
• 
Persists (as non-serious AE):  Subject 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:  Subject recovered completely from the SAE (the date of recovery should be entered 
as the SAE resolution date) 
• 
Fatal:  Subject died (the date of death should be entered as the SAE resolution date) 
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. All platelet count results must be reviewed 
promptly (within 48 hours of receipt) by the Investigator or the designee 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 interruption rule of 75,000/mm3 as specified in Section 8.6.3. Any case of a platelet 
count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is considered an adverse event of 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
70 
special interest and should be reported in an expedited fashion to the Sponsor as per Sections 9.3.3.1 and 
9.4.1). 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per Section 8.6.1. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per Section 8.6.2. 
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 subject 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 subject’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 subject’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 
Study Drug (ISIS 703802) errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the subject was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. Dosing details should be captured on the Dosing 
eCRF.  If the subject takes a dose of Study Drug that exceeds protocol specifications and the subject 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 
Subjects must continue to use appropriate contraception with their partners, or refrain from sexual 
activity, as described in Section 6.3.1.  If a subject becomes pregnant or a pregnancy is suspected, or if a 
male subject 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 by designating as ‘Follow-up’ on the Pregnancy 
Forms and reported within 24 hours.  Payment for all aspects of obstetrical care, child or related care will 
be the subject’s responsibility.  Female subjects:  If a suspected pregnancy occurs while on the Study 
(including follow-up), a pregnancy test will be performed.  The subject with a confirmed pregnancy will 
be immediately withdrawn from treatment with Study Drug.  However, the subject 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 subject in getting obstetrical care and the progress of the pregnancy will be followed until the outcome 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
71 
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.  Follow-up will be performed to the 
extent permitted by the applicable regulations and privacy considerations.  Male subjects:  The progress 
of the pregnancy of a male subject’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 
the applicable regulations and privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
10.1.1 
Primary Endpoint 
• 
The effect of ISIS 703802 on the percent change from Baseline in fasting triglyceride levels (TG) 
at week 27 
10.1.2 
Secondary Endpoints 
• 
Change from Baseline in AUC plasma glucose, serum insulin, serum C-peptide, free fatty acid, 
serum ghrelin, GIP, GLP-1, and PYY and incretin hormones in response to a mixed meal test 
(MMT) 
• 
Change from Baseline in lipids and lipoproteins including high-density lipoprotein cholesterol 
(HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very low-density 
lipoprotein cholesterol (VLDL-C), non-HDL-C, apolipoprotein B (apoB), apolipoprotein B-48 
(apoB-48), apolipoprotein B-100 (apoB-100), apolipoprotein A-1 (apoA-1), apolipoprotein C-III 
(apoC-III :total, chylomicron, VLDL, LDL and HDL), Lipoprotein a [Lp(a)], free fatty acids 
(FFA), and glycerol levels, lipoprotein particle size/number 
• 
Change from Baseline in glycosylated hemoglobin (HbA1c) 
• 
Change from Baseline in homeostasis model assessment-estimated insulin resistance (HOMA-IR) 
• 
Change from Baseline in adiponectin and leptin 
• 
Change from Baseline in hepatic fat fraction (as assessed by magnetic resonance imaging [MRI]) 
• 
Changes from Baseline in body fat distribution for various areas in the body as measured by 
skinfold thickness and DEXA; VAT and SAT as measured by MRI; body weight, waist 
circumference and waist/hip ratio 
• 
Change from Baseline in quality of life and pain score 
10.2 
Sample Size Considerations 
There is no statistical rationale for the selected sample size.  The sample size is selected based upon prior 
experience with ISIS 703802 to ensure that the safety, tolerability and efficacy of ISIS 703802 can be 
explored in an ultra-rare condition before enrolling subjects in a larger study.   
10.3 
Populations 
Safety Set:  All subjects who are enrolled and receive at least 1 dose of Study Drug.  PK Set:  All subjects 
who receive at least 1 dose of Study Drug and have at least 1 evaluable PK sample. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
72 
10.4 
Definition of Baseline 
For fasting lipid measurements, the Baseline is defined as the average of Day 1 pre-dose assessment and 
the last measurement prior to Day 1. 
For other measurements, Baseline will be the last non-missing assessment prior to the first dose of 
Study Drug. 
10.5 
Interim Analysis and Early Stopping Guidelines 
Since the study is open labeled no interim analysis will be performed to inform early stopping guidelines.  
10.6 
Planned Methods of Analysis 
Summary tabulations will be provided for disposition, demographic, baseline, efficacy, and safety data as 
noted in the following sections. 
All eCRF data, lab data, and 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.   
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by treatment 
group.  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. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term and 
severity. 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug received will be summarized.  Patient incidence rates of all 
AEs will be tabulated by MedDRA system organ class, and by MedDRA preferred term.  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. 
10.6.2.2 
Clinical Laboratory Data 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) with 
differential, coagulation panel, complement, etc., will be summarized by study visit.  These safety 
variables will also be presented as change and percent change from Baseline over time after Study Drug 
administration, as appropriate.  In addition, the number of subjects who experience abnormalities in 
clinical laboratory evaluations will be listed. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
73 
10.6.2.3 
Vital Signs and Examinations 
Vital signs, weight, and ECG measures will be summarized by study visit. 
10.6.3 
Efficacy Analysis 
Change at week 27 relative to Baseline will be summarized for: 
• 
Fasting TG 
• 
MTT (plasma glucose, serum insulin, serum C-peptide, FFA, serum ghrelin, GIP, GLP-1 and 
PYY) 
• 
Glycosylated hemoglobin  
• 
HOMA-IR 
• 
24-hr glucose 
• 
Adiponectin and leptin 
• 
HFF 
• 
Fat distribution 
10.6.4 
Pharmacokinetic Analysis 
The plasma PK of ISIS 703802 (as total full length oligonucleotides, including, fully conjugated, partially 
conjugated, and unconjugated ISIS 703802) will be assessed following multiple-dose SC administration.  
The plasma trough levels of ISIS 703802 during treatment period and those during post-treatment follow 
up period will be descriptively summarized with stratification by subject immunogenicity status if 
applicable.  
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not evaluable, and 
when applicable, titer of anti- ISIS 703802 antibodies) before, during, and after treatment with ISIS 
703802 will be listed.  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 and study day. 
 
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.  
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
74 
10.6.5 
Pharmacodynamic Analysis 
The following parameters will be measured throughout the trial and change at week 27 relative to 
Baseline will be summarized: 
• 
ANGPTL3 
• 
HDL-C  
• 
LDL-C 
• 
TC  
• 
VLDL-C   
• 
non-HDL-C  
• 
apoB  
• 
apoB-48  
• 
apoB-100 
• 
apoA-1  
• 
apoC-III 
• 
Lp(a)  
• 
FFA  
• 
Glycerol levels 
• 
Lipoprotein particle size/number 
10.6.6 
Additional Analyses 
Additional analyses may be performed not specified in this open label study protocol from the data 
available. 
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 or designee. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written informed 
consent from the subject or legally acceptable representative after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any Study Drug ISIS 703802 are administered.  The subject or legally acceptable 
representative must be given sufficient time to consider whether to participate in the study.   
The acquisition of informed consent and the subject’s agreement or refusal to notify his/her primary care 
physician should be documented in the subject’s medical records and the informed consent form should 
be signed and personally dated by the subject or a legally acceptable representative 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 subject or legally 
acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the informed consent form to the 
subject and must allow for questions.  Thereafter, both the subject or legally acceptable representative and 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
75 
the witness must sign the informed consent form to attest that informed consent was freely given and 
understood. 
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 subject 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 or designee 
before recruitment of subjects into the study and shipment of Study Drug.  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 or designee before recruitment of subjects 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 SAEs occurring at the Study Center and other AE 
reports received from the Sponsor or designee, 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 or designee. 
11.4 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report forms or 
other documents submitted to the Sponsor or designee, subjects should be identified by initials (if 
permitted by local law) and a subject identification number only.  Documents that are not for submission 
to the Sponsor or designee (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 subject’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 subject to permit named representatives to have access to his/her 
study-related records without violating the confidentiality of the subject. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
76 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  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 subjects or the conduct of the trial.  The 
Investigator must send a copy of the approval letter from the IEC/IRB to the Sponsor or designee. 
12.2 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves the right to 
terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor or designee 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 or designee. 
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 subject’s case report form 
data are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  Case report form entries may be 
considered source data if the case report form is the site of the original recording (i.e., there is no other 
written or electronic record of data).   
The Investigator and Study Center staff 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 or designee 
and/or applicable regulatory authorities.  Elements should include: 
• 
Subject files containing completed case report forms, 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 or 
designee 
• 
If drug supplies are maintained at the Study Center, proof of receipt, Study Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug product 
reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be maintained 
and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or designee 
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 or designee. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
77 
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., case report forms and other pertinent data) provided that subject confidentiality is 
respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms 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 subject medical records and other study-related records needed to verify the entries on the case 
report forms. 
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 case report forms, 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 (or designees).  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 subject data 
received by the Sponsor or designee.  During this review, subject 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 or designee. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case report 
form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Whenever possible, the trade name rather than the 
generic name for concomitant medications should be recorded and if possible, in English.  Generic names 
are acceptable if the trade name is unknown.  Combination medications should be recorded using their 
trade name in English if possible. 
All written information and other material to be used by subjects 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.  Subjects 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 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
78 
13. 
REFERENCES 
Ahmad Z, Subramanyam L, Szczepaniak L, Simha V, Adams-Huet B, Garg A.. Cholic acid for hepatic steatosis in 
patients with lipodystrophy: a randomized, controlled trial. Eur J Endocrinol. 2013 Apr 15;168(5):771-8. doi: 
10.1530/EJE-12-0969. Print 2013 May.  
Akinci B, Onay H, Demir T, Savas-Erdeve S, Gen R, Simsir IY, Keskin FE, Erturk MS, Uzum AK, Yaylali GF, 
Ozdemir NK, Atik T, Ozen S, Yurekli BS, Apaydin T, Altay C, Akinci G, Demir L, Comlekci A, Secil M, Oral EA. 
Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial 
lipodystrophy. Metabolism. 2017 Jul;72:109-119. doi: 10.1016/j.metabol.2017.04.010. Epub 2017 Apr 27.  
Ajluni N, Dar M, Xu J, Neidert AH, Oral EA. Efficacy and Safety of Metreleptin in Patients with Partial 
Lipodystrophy: Lessons from an Expanded Access Program. J Diabetes Metab 2016; 7: 659  
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Bidault G, Garcia M, Vantyghem MC, Ducluzeau PH, Morichon R, Thiyagarajah K, Moritz S, Capeau J, Vigouroux 
C, Béréziat V. Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro 
endothelial dysfunction. Arterioscler Thromb Vasc Biol 2013.  
Brandt TA, Lee RG, Digenio A, Graham MG, Crooke RM, Hughes SG, Singleton W, Witztum JL, Tsimikas S. 
ISIS-ANGPTL3RX, an antisense inhibitor to angiopoietin-like 3, reduces plasma lipid levels in mouse models and 
in healthy human volunteers. Atherosclerosis 2015; 241: e30-e31.  
Büller HR, Cohen AT, Davidson B, Decousus H, Gallus AS, Gent M, Pillion G, Piovella F, Prins MH, Raskob GE. 
Idraparinux versus standard therapy for venous thromboembolic disease. New England Journal of Medicine 2007; 
357: 1094-1104. 
Chan JL and Oral EA. Clinical classification and treatment of congenital and acquired lipodystrophy. Endocr Pract 
2010; 16: 310-323. Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annual Review 
of Pharmacology and Toxicology 1996; 36: 107-129. 
Cobelli C, Toffolo GM, Dalla MC, Campioni M, Denti P, Caumo A, Butler P, Rizza R. Assessment of beta-cell 
function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral 
glucose tests. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E1-E5. Epub 2007 Mar 6. 
Committee for Orphan Medicinal Products (COMP) meeting report on the review of applications for orphan 
designation June 2012 
Diker-Cohen Cochran E, GordenT P, Brown RJ. Partial and generalized lipodystrophy: Comparison of baseline 
characteristics and response to metreleptin. J Clin Endocrinol Metab 2015.  
Dorato MA and Engelhardt JA. The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and 
definition(s). Regul Toxicol Pharmacol. 2005; 42(3): 265-74. 
Dunnigan MG, Cochrane MA, Kelly A, Scott JW. Familial lipoatrophic diabetes with dominant transmission. A new 
syndrome. Q J Med 1974; 43: 33-48.  
Everds N, Li N, Bailey K, Fort M, Stevenson R, Jawando R, Salyers K, Jawa V, Narayanan P, Stevens E, He C, 
Nguyen MP, Tran S, Doyle N, Poitout-Belissent F, Jolette J, Xu C, Sprugel K. Unexpected thrombocytopenia and 
anemia in cynomolgus monkeys induced by a therapeutic human monoclonal antibody. Toxicol Pathol. 2013; 
41(7):951-69. doi: 10.1177/0192623312474727. Epub 2013 Mar 7. 
FDA 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 
https://www.fda.gov/downloads/Guidances/UCM174090.pdf   


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
79 
Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004 Mar 18; 350(12):1220-34.  
Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J J Clin Endocrinol Metab. 
2011 Nov;96(11):3313-25. doi: 10.1210/jc.2011-1159. Epub 2011 Aug 24.  
Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AA. 
Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-methoxyethyl) modified antisense 
oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 1419-1428. 
Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, Yu R, Hurh E, Paz E, McEvoy BW, Baker BF, Pham 
NC, Digenio A, Hughes SG, Geary RS, Witztum JL, Crooke RM, Tsimikas S. Cardiovascular and Metabolic Effects 
of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017 Jul 20;377(3):222-232. doi: 
10.1056/NEJMoa1701329. Epub 2017 May 24. 
Handelsman Y, Oral EA, Bloomgarden ZT, Brown RJ, Chan JL, Einhorn D, Garber AJ, Garg A, Garvey WT, 
Grunberger G, Henry RR, Lavin N, Tapiador CD, Weyer C; American Association of Clinical Endocrinologists. 
The clinical approach to the detection of lipodystrophy - An AACE Consensus Statement. Endocr Pract. 2013 Jan-
Feb;19(1):107-16  
Hegele RA. Premature atherosclerosis associated with monogenic insulin resistance. Circ 2001; 103: 2225-2229.  
Hegele RA, Joy TR, Al-Attar SA, Rutt BK. Thematic review series: Adipocyte Biology. Lipodystrophies: Windows 
on adipose biology and metabolism. J Lipid Res 2007; 48: 1433-1444.  
Henry SP, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF. Chemically modified oligonucleotides exhibit 
decreased immune stimulation in mice. J Pharmacol Exp Ther. 2000 Feb;292(2):468-79.  
Huang-Doran I, Sleigh A, Rochford JJ, O'Rahilly S, Savage DB. Lipodystrophy: metabolic insights from a rare 
disorder. J Endocrinol. 2010 Dec;207(3):245-55. doi: 10.1677/JOE-10-0272. Epub 2010 Sep 24 
Huszar D, Varban ML, Rinninger F, Feeley R, Arai T, Fairchild-Huntress V, Donovan MJ, Tall AR. Increased LDL 
cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. 
Arterioscler Thromb Vasc Biol. 2000 Apr;20(4):1068-73. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. FEBS Letters 1987 May 11; 215(2): 327-30. 
Inukai K, Nakashima Y, Watanabe M, Kurihara S, Awata T, Katagiri H, Oka Y, Katayama S. ANGPTL3 is 
increased in both insulin-deficient and -resistant diabetic states. Biochem Biophys Res Commun. 2004 May 
14;317(4):1075-9.  
Köbberling J, Willms B, Kattermann R, Creutzfeldt W. Lipodystrophy of the extremities. A dominantly inherited 
syndrome associated with lipatrophic diabetes. Humangenetik. 1975 Sep 10;29(2):111-20.  
Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM. Carbohydrate-restricted diets high 
in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids.Am J 
Clin Nutr. 2005 Apr;81(4)762-72. 
Martin-Campos JM, Roig R, Mayoral C, Martinez S, Martí G, Arroyo JA, Julve J, Blanco-Vaca F. Identification of 
a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without 
APOB mutation. Clin Chim Acta. 2012 Mar 22;413(5-6):552-5. doi: 10.1016/j.cca.2011.11.020. Epub 2011 Nov 29. 
McKay RA, Miraglia LJ, Cummins LL, Owens SR, Sasmor H, Dean NM. Characterization of a potent and specific 
class of antisense oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem. 1999 Jan 
15;274(3):1715-22.  
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
80 
Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G, Gabiati C, Pigna G, Sepe ML, Pannozzo 
F, Lütjohann D, Fazio S, Jauhiainen M, Ehnholm C, Arca M. Mutations in the ANGPTL3 gene and familial 
combined hypolipidemia: A clinical and biochemical characterization. J Clin Endocrinol Metab. 2012 
Jul;97(7):E1266-75. doi: 10.1210/jc.2012-1298. Epub 2012 Jun 1.  
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.  
Moran LJ, Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Clifton PM. The satiating effect of dietary 
protein is unrelated to postprandial ghrelin secretion. J Clin Endocrinol Metab. 2005 Sep;90(9)5205-11. Epub 2005 
Jul 12. 
Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry 
AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, 
Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S. Exome sequencing, 
ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010 Dec 2;363(23):2220-7. doi: 
10.1056/NEJMoa1002926. Epub 2010 Oct 13. 
Myalept, Package Insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125390s000lbl.pdf (accessed 
February 5, 2018). 
National Organization for Rare Disorders [NORD]. The Physician’s Guide to Lipodystrophy Disorders 2012.  
Nolis T. Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. J of Human 
Gen 2014; 59:16-23.  
Noto D, Cefalu AB, Valenti V, Fayer F, Pinotti E, Ditta M, Spina R, Vigna G, Yue P, Kathiresan S, Tarugi P, 
Averna MR. Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia. 
Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):805-9. doi: 10.1161/ATVBAHA.111.238766. Epub 2012 Jan 12.  
Pisciotta L, Favari E, Magnolo L, Simonelli S, Adorni MP, Sallo R, Fancello T, Zavaroni I, Ardigò D, Bernini F, 
Calabresi L, Franceschini G, Tarugi P, Calandra S, Bertolini S. Characterization of three kindreds with familial 
combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet. 2012 Feb 
1;5(1):42-50. doi: 10.1161/CIRCGENETICS.111.960674. Epub 2011 Nov 7. 
Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, Schmidt K, Zhao C, Aghajan M, Murray HF, Riney S, 
Booten SL, Murray SF, Gaus H, Crosby J, Lima WF, Guo S, Monia BP, Swayze EE, Seth PP. Targeted delivery of 
antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in 
mice. Nucleic Acids Res. 2014 Jul;42(13):8796-807. doi: 10.1093/nar/gku531. Epub 2014 Jul 3. 
Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines DB, Gernsheimer 
TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino 
M, Watson S, Young J, Kuter DJ. International consensus report on the investigation and management of primary 
immune thrombocytopenia. Blood. 2010 Jan 14;115(2):168-86. doi: 10.1182/blood-2009-06-225565. Epub 2009 
Oct 21.  
Robbins AL and Savage DB. The genetics of lipid storage and human lipodystrophies. Trends Mol Med. 2015 
Jul;21(7):433-8. doi: 10.1016/j.molmed.2015.04.004. Epub 2015 May 12.  
Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH, Cohen JC. Rare loss-of-function 
mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009 
Jan;119(1):70-9. doi: 10.1172/JCI37118. Epub 2008 Dec 15. 
Schreyer SA, Vick C, Lystig TC, Mystkowski P, LeBoeuf RC. LDL receptor but not apolipoprotein E deficiency 
increase diet-induced obesity and diabetes in mice. Am J Physiol Endocrinol Metab. 2002 Jan;282(1):E207-14. 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
81 
Shulman, GI.  Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease N Engl J Med 2014; 
371:1131-1141. 
Sleigh A, Stears A, Thackray K, Watson L, Gambineri A, Nag S, Campi VI, Schoenmakers N, Brage S, Carpenter 
TA, Murgatroyd PR, O'Rahilly S, Kemp GJ, Savage DB. Mitochondrail oxidative phosphorylation is impaired in 
patients with congenital lipodystrophy. J Clin Endocrinol Metab. 2012 Mar;97(3):E438-42. doi: 10.1210/jc.2011-
2587. Epub 2012 Jan 11.  
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Tsuchiya H, Ikeda Y, Ebata Y, et al. Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice. 
Hepatology 2012: 56(4): 1319-1330. 
Vatier C, Bidault G, Briand N, et al. What the genetics of lipodystrophy can teach us about insulin resistance and 
diabetes. Curr Diab Rep 2013; 13 Sep (online).  
Wang Y, McNutt MC, Banfi S, Levin MG, Holland WL, Gusarova V, Gromada J, Cohen JC, Hobbs HH. Hepatic 
ANGPTL3 regulates adipose tissue energy homeostasis. Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11630-5. 
doi: 10.1073/pnas.1515374112. Epub 2015 Aug 24. 
Zhang H, Löwenberg EC, Crosby JR, MacLeod AR, Zhao C, Gao D, Black C, Revenko AS, Meijers JC, Stroes ES, 
Levi M, Monia BP. Inhibition of the intrinsic coagulation pathway Factor XI by antisense oligonucleotides: a novel 
antithrombotic strategy with lowered bleeding risk. Blood. 2010 Nov 25;116(22):4684-92. doi: 10.1182/blood-2010-
04-277798. Epub 2010 Aug 31.  
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
82 
14. 
APPENDICES 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
83 
 
 
 
 
 
 
 
Appendix A Schedule of Procedures 
 
 
 
 
 
 
 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
84 
Appendix A  
Schedule of Procedures  
 
 
 
 Screening 
Treatment Period 
Follow-up Period 
Run-in# 
Qual† 
Study Week 
-6 to -1 
-1 to 0 
1 
5 
9 
13 
17 
21 
25 
27/ET 
4* 
8* 
13* 
Study Day 
-42 to -1 
-7 to -1 
1 
29 
57 
85 
113 
141 
169 
183 
*Weeks from the end of 
treatment periodo 
Visit and Testing Window +/- Days 
0 
0 
0 
2 
2 
2 
3 
3 
3 
0 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Testingp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination a 
X 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
Body Weight and Height b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist and hip circumference 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
DEXA Scan 
Xd 
 
 
 
X 
 
 
 
X 
 
 
 
12- lead ECG (triplicate) 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Ultrasound  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Mixed Meal Test c 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
MRI  
Xd 
 
 
 
X 
 
 
 
X 
 
 
 
24-Hour Urine for Creatinine 
Clearance and Proteinq 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Extended Urinalysis e 
X 
 
EVERY 14 DAYS (+/- 2 days) e, f 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine and Cys-C i, j, k 
X 
 
EVERY 14 DAYS (+/- 2 days) f, i 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel j , k 
X 
 
EVERY 14 DAYS (+/- 2 days) f 
X 
X 
X 
X 
X 
X 
X 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
85 
Appendix A  
Schedule of Procedures Continued 
 
 Screening 
 
Treatment Period 
 Follow-up Period 
 
 
Run-in# 
Qual† 
Study Week 
-6 to -1 
-1 to 0 
1 
5 
9 
13 
17 
21 
25 
27/ET 
4* 
8* 
13* 
Study Day 
-42 to -1 
-7 to -1 
1 
29 
57 
85 
113 
141 
169 
183 
*Weeks from the end of 
treatment periodo 
Visit and Testing Window +/- Days 
0 
0 
0 
2 
2 
2 
3 
3 
3 
0 
3 
3 
3 
Hematology 
X 
 
EVERY 14 DAYS (+/- 2 days) f 
Xh 
Xh 
Xh 
Coagulation 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Liver Biomarkers 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 703802 l 
 
 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
X 
Anti-ISIS 703802 Antibodies 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
FSH (women only, if applicable) j, m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test m 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Archived Serum & Plasma Samples 
j, n 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
PD Panel j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Extended Lipid Panel j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1C j 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Quality of Life Assessment 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Widespread Pain Diary 
 
X 
TO BE DONE AT OUTPATIENT VISITS  
X 
X 
X 
Study Drug:  SC Injection 
 
 
WEEKLY SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 
through Week 26/Day 176) 
 
 
 
 
Adverse Events 
TO BE COLLECTED FROM TIME OF INFORMED CONSENT TO END OF FOLLOW-UP PERIOD 
Concomitant Medication 
TO BE COLLECTED FROM TIME OF INFORMED CONSENT TO END OF FOLLOW-UP PERIOD 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
86 
Appendix A  
Schedule of Procedures Continued 
# Subjects on stable diet known to the investigator and followed at the site may go from Screening to qualification without the diet run-in period. 
† Qual =Qualification  
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
Full physical exam will be performed at the screening visit and an abbreviated physical exam will be performed during treatment and follow-up periods. 
b     Height only required at Screening 
c     Mixed Meal Test-refer to Appendix E for further details 
d     MRI and DEXA scan will only be performed during Screening after all other eligibility criteria are met.  MRI should be performed 10 days (+/- 2 days) prior to 
anticipated Day 1 date to allow time for result reporting and analysis.  DEXA scan should be performed as close to anticipated Day 1 date as possible. 
e 
All tests listed in Appendix B under Extended Urinalysis should be performed, including routine urinalysis, urine microscopy, UACR and UPCR. 
f 
Assessments and procedures to be conducted by either a home healthcare service or the Study Center.  Subject Study Center visits must be no more than 
4 weeks apart during the treatment period. 
g 
Urine samples for renal biomarkers will be collected.  Sample analysis will be conducted in accordance with Safety Monitoring for Renal Function 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values are taken every 14 days (+/- 2 days) for 6 weeks after last dose of Study Drug, then at Week 
8 and Week 13 Follow-up visits.   
i 
Serum Creatinine and Cys-C will be collected as a part of chemistry panel at visits when chemistry panel is performed, or as stand-alone samples at time 
points when a chemistry panel is not performed. 
j 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours, unless tests are repeated for safety reasons. 
k 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen should be re-drawn as soon as possible (ideally within 7 days).  All platelet count results will be reviewed promptly (within 48 hours of receipt) by the 
Investigator as per Section 6.2.1.  Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
l      Refer to Appendix C for PK Sampling schedule. 
m 
Women who are not surgically sterile or post-menopausal. 
n 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or 
chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) and will be retained until completion of the final 
study report. 
o     Treatment period is defined as the time from the first dose through one dosing interval post last dose. 
p     Genetic testing will only be performed for eligibility if there is no documented genetic testing in medical history. 
q     24-hour urine sample for creatinine clearance and protein should also be obtained in the event of an eGFR (CKD-EPI) value meeting criteria specified in 
Sections 8.5.2 and 8.6.2. 
Time (time is in reference to Study Drug administration): 
1 Pre-dose 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
87 
 
 
 
 
 
 
 
Appendix B List of Laboratory Analytes 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
88 
Appendix B 
List of Laboratory Analytes 
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 
• 
Creatinine kinase 
• 
GGT 
• 
Cys-C 
 
PD Panel 
• 
ANGPTL3 
• 
Insulin 
• 
Proinsulin 
• 
C-peptide 
• 
Fructosamine 
• 
Glycated albumin 
• 
Delipidated Free Glycerol 
• 
Fasting Plasma Glucose 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
Screening Tests 
• 
Hepatitis B 
surface antigen 
• 
Hepatitis C 
antibody 
• 
HIV antibody 
• 
FSH (women 
only) 
• 
Serum βhCG 
• 
TSH 
• 
Free T4 
 
 
Extended Lipid  Panel 
• 
Total Cholesterol 
(TC) 
• 
LDL cholesterol 
(LDL-C) 
• 
HDL cholesterol 
(HDL-C) 
• 
Triglycerides (TG) 
• 
VLDL cholesterol 
(VLDL-C) 
• 
Non-HDL 
cholesterol (Non-
HDL-C) 
• 
Lp(a) 
• 
FFA 
• 
ApoB 
• 
ApoB-48 
• 
ApoB-100 
• 
Apo A-1 
• 
ApoCIII (total, 
chylomicron, 
LDL, HDL, 
VLDL) 
• 
Delipidated Free 
Glycerol 
• 
Ceramides 
• 
Sphingolipids 
• 
Diacyglycerol 
• 
Lipoprotein 
particle analysis 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, MCHC 
• Platelets 
• White blood cells 
• WBC Differential (% and 
absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Pharmacokinetics1 
• ISIS 703802 levels in 
plasma 
 
Immunogenicity 
• Anti-ISIS 703802 
antibodies 
 
Liver Biomarkers (Biomarkers 
of liver apoptosis and fibrosis) 
• CK18  
• PIIINP  
 
Inflammatory 
• hs-CRP 
• IL-6 
• IFN gamma 
• TNF alpha 
• Leptin 
• Adiponectin 
 
Genetic Testing 
• Genetic sequencing of FPL 
causing genes3 
 
Extended Urinalysis 
• 
Routine Urinalysis 
- 
Color 
- 
Appearance 
- 
Specific gravity 
- 
pH 
- 
Protein 
- 
Blood 
- 
Glucose 
- 
Ketones 
- 
Bilirubin 
- 
Urobilinogen 
- 
Leukocyte esterase 
- 
Nitrate 
• 
Microscopic examination 
• 
P/C Ratio (UPCR) 
• 
A/C Ratio (UACR) 
 
24-Hour Urine Test 
• 
Creatinine clearance 
• 
Protein 
• 
Albumin 
 
Mixed Meal Test 
• 
Plasma glucose 
• 
FFA 
• 
C-peptide 
• 
Insulin 
• 
Serum ghrelin 
• 
GIP 
• 
GLP-1 
• 
PYY 
• 
Incretin hormones 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation purposes, 
stability assessments, metabolite assessments, or to assess other actions of ISIS 703802 with plasma constituents 
2 
All samples will be collected, handled and stored under the conditions specified for the assays. Please refer to the study 
Laboratory Manual for details on the appropriate handling and storage methods for biomarker and other samples. 
3 
Blood will be collected to assess genetic evidence of FPL (e.g., mutations in LMNA, PPAR-γ, AKT2, CIDEC, PLIN1 
genes).  May not be collected if adequate genetic data are available in medical history or if patient does not consent to 
genetic testing 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
89 
 
 
 
 
 
 
Appendix C PK Sampling Schedule  
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
90 
Appendix C PK Sampling Schedule  
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
5 
9 
13 
17 
21 
25 
27 
4* 
8* 
13* 
Study 
Day 
D1 
D29 
D57 
D85 
D113 
D141 
D169 
D183 
* Weeks from the end of treatment 
period1 
 
 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
Anytime 
Anytime 
Note:  D, Day 
1    Treatment period is defined as the time from the first dose through one dosing interval post last dose 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
91 
 
 
 
 
 
 
 
Appendix D Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
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 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
93 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
94 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
95 
 
 
 
 
 
 
 
 
 
 
Appendix E Mixed Meal Test 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
96 
Appendix E Mixed Meal Test  
At Qualification, 3 months and end of study, subjects enrolled will undergo a meal tolerance test (MTT) 
as follows: subjects will consume a standardized meal the evening before the test (750 kcal; 20% of 
energy from protein, 30% from fat, and 50% from carbohydrate) and refrain from consuming alcohol for 
72 h.  
A cannula will be inserted into a forearm vein, and an overnight fasting (minimum 10 hours) venous 
blood sample will be taken between 8:00 AM and 10:00 AM for measurement of plasma glucose, FFA,         
C-peptide and insulin concentrations and serum ghrelin, GIP, GLP-1, and PYY.  Incretin hormones will 
be measured using a multiplex assay (EMD Millipore, Billerica, MA).  The tubes for the incretin 
hormones will contain Pefabloc SC (Sigma-Aldrich, St. Louis, MO) and DPP-IV inhibitor (EMD 
Millipore, Billerica, MA) to inhibit DPP-IV and other proteases.  The change in ratings from Baseline 
will be quantified.  
Subjects will then consume a liquid load of Optifast (Optifast; Novartis, Minneapolis, MN; 474 ml, 320 
kcal, 50% carbohydrate, 35% protein, 15% fat) within a 15-min period.  Additional blood samples will be 
taken at 10, 20, 30, 60, 90, 120, 150, 180, 240 and 300 min after meal consumption.  VAS will be 
completed at 180 minutes and 300 min.  To calculate the insulin sensitivity index (SI), the oral minimal 
model for glucose will be used; and to calculate the hepatic insulin extraction, oral minimal model for 
insulin and c-peptide will be used [Cobelli et al, 2007]. Subjects will complete a validated visual analogue 
scale (VAS) questionnaire to assess subjective hunger at 0, 180 and 300 minutes [Luscombe-Marsh et al, 
2005; Moran et al, 2005]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
97 
 
 
 
 
 
 
 
 
 
 
Appendix F Laboratory Tests to Be Performed in the Event of a 
Platelet Count ˂ 100,000/mm3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ISIS 703802-CS5 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
16 February 2018 
 
98 
Appendix F 
Laboratory Tests to Be Performed in the Event of a Platelet Count ˂ 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 
 
 
 
 


55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142   
www.akceatx.com 
 
Page 1 of 2 
ISIS 703802-CS5: Administrative Clarification Letter 1 to Protocol Amendment 1 
ISIS 703802-CS05:  Administrative Clarification Letter 1 to Protocol Amendment 1 
 
11 September 2018 
 
RE: Protocol ISIS 703802-CS5: An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial Lipodystrophy, Protocol Amendment 1 
dated 16 February 2018 
Dear Investigators: 
The following administrative clarifications are being issued for Protocol ISIS 703802-CS5 Amendment 1. 
 
Administrative Clarification 1 – Section 6.2.1 Physical Exams and Vital Signs 
Current Text: 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures (Appendix A). 
Vital signs should include weight, blood pressure (BP), pulse rate, respiratory rate and body temperature. BP 
and pulse rate will be recorded after the subject has been in a sitting position for at least 5 minutes. BP should 
always be measured on the same arm (preferentially on the left arm). Height will be measured at Screening. 
Clarification: (new text indicated in bold) 
Physical exams, vital signs, and skin fold measurements will be performed as indicated in the Schedule of 
Procedures (Appendix A). Vital signs should include weight, blood pressure (BP), pulse rate, respiratory rate 
and body temperature. BP and pulse rate will be recorded after the subject has been in a sitting position for at 
least 5 minutes. BP should always be measured on the same arm (preferentially on the left arm). Height will 
be measured at Screening. Skinfold measurements will be recorded as per the Schedule of Procedures 
(Appendix A) starting at Day 1 Pre-dose. Skinfold measurements will be collected from each subject’s 
right mid anterior thigh and right tricep.  
Rationale: 
The secondary endpoints include “Changes from Baseline in body fat distribution for various areas in the 
body as measured by skinfold thickness and DEXA.”  The purpose of this clarification it to provide omitted 
details regarding the collection of skinfold measurements that were missing from Section 6: Study 
Procedures. This measurement will occur at every visit in which a physical exam (full or abbreviated) occurs. 
 
Administrative Clarification 2 – Appendix A Schedule of Procedures – Skinfold Measurements 
Current Text: 
None. 


55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142   
www.akceatx.com 
 
Page 2 of 2 
ISIS 703802-CS5: Administrative Clarification Letter 1 to Protocol Amendment 1 
Clarification: (new text indicated in bold) 
Skinfold Measurements: Performed at Study Day 1 (Pre-dose) and at Weeks 5, 13 and 27/ET, and 
during the Follow Up Period at Weeks 4 and 13. 
Rationale: 
The secondary endpoints include “Changes from Baseline in body fat distribution for various areas in the 
body as measured by skinfold thickness and DEXA.” It has come to our attention that the details of the 
collection and specific timepoints of collecting skinfold measurements were missing from Appendix A: 
Schedule of Procedures. Skin fold measurements will occur as part of the physical exam and therefore, this 
measurement will occur at every visit in which a physical exam (full or abbreviated) occurs. 
 
Summary 
This Administrative Clarification Letter serves to align the planned secondary endpoints with Section 6: 
Study Procedures and Appendix A: Schedule of Procedures.  It is noted that no safety assessments or 
procedures have been added or removed.  This clarification does not affect the rights, safety, or well-being of 
study participants. 
 
Sincerely,  
 
 
Akcea Therapeutics, Inc.  
 
cc: ISIS 703802-CS5 Study Coordinators, ISIS 703802-CS5 TMF 


55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142   
www.akceatx.com 
 
Page 1 of 2 
ISIS 703802-CS05: Administrative Clarification Letter 2 to Protocol Amendment 1 
ISIS 703802-CS5:  Administrative Clarification Letter 2 to Protocol Amendment 1 
02 October 2018 
RE: Protocol ISIS 703802-CS5: An open-label Phase 2 Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) 
Administered Subcutaneously to Subjects with Familial Partial Lipodystrophy, Protocol Amendment 1 
dated 16 February 2018 
Dear Investigators: 
The following administrative clarifications are being issued for Protocol ISIS 703802-CS5 Amendment 1. 
 
Administrative Clarification 1 – Appendix A Schedule of Procedures – Footnote H 
Current Text: 
During follow-up period, hematology sampling for platelet values are taken every 14 days (+/- 2 days) for 6 
weeks after last dose of Study Drug, then at Week 8 and Week 13 Follow-up visits.  
Clarification: (new text indicated in bold) 
During the treatment period, hematology sampling for platelet values are taken every 14 days (+/- 2 days) from 
first dose through 6 weeks post treatment period, then at Week 8, and Week 13 Follow-up visits.  
Rationale: 
Clarification to footnote H of the Schedule of Procedures in order to align with the timing for hematology 
sampling following the treatment period. 
 
Summary 
This Administrative Clarification Letter serves to align the timing for hematology sampling as outlined in the 
Schedule of Events Table in Appendix A. It is noted that no safety assessments or procedures have been added or 
removed.  This clarification does not affect the rights, safety, or well-being of study participants. 
 
Sincerely,  
 
 
Akcea Therapeutics, Inc.  
 
cc: ISIS 703802-CS5 Study Coordinators, ISIS 703802-CS5 TMF