A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Finding Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered Subcutaneously to Subjects With Hypertriglyceridemia, Type 2 Diabetes Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease (NAFLD)
Phase: PHASE2
Conditions: NAFLD, Diabetes Mellitus, Type 2, Hypertriglyceridemia, Fatty Liver, Nonalcoholic
Sponsor: Akcea Therapeutics

 
           Official Title: 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose 
Finding Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered 
Subcutaneously to Subjects with Hypertriglyceridemia, Type 2 
Diabetes Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease 
(NAFLD) 
NCT Number: NCT03371355 
Document Dates: 
 
Protocol Amendment 3 – 21 March 2019 
 
 

 
  
 
 
 
Sponsor: 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA  02210 
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
 
 
ISIS 703802-CS2 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose 
Finding Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered 
Subcutaneously to Subjects with Hypertriglyceridemia, Type 2 Diabetes 
Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease (NAFLD) 
 
Protocol Amendment 3– 21 March 2019 
 
 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
21 March 2019 
 
3 
ISIS 703802-CS2 
Protocol Number ISIS 703802-CS2 
Protocol Amendment 3 
Clinical Phase:  2 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose 
Finding Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered 
Subcutaneously to Subjects with Hypertriglyceridemia, Type 2 Diabetes 
Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease (NAFLD) 
Trial Sponsor: 
Akcea Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
Key sponsor contact:  
 
 - Akcea Therapeutics, 
Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
 
Phone: 
 
E-mail: 
 
Sponsor Medical Monitor: 
 MD 
 - Akcea 
Therapeutics, Inc. 
22 Boston Wharf Road, 9th Floor 
Boston, MA  02210 
Phone: 
 
Mobile: 
 
E-mail: 
 
Date: 
21 March 2019 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
21 March 2019 
 
4 
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-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
21 March 2019 
 
5 
Protocol Signature Page 
 
Protocol Number:  ISIS 703802-CS2  
Protocol Title:  
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Finding 
Study of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered 
Subcutaneously to Subjects with Hypertriglyceridemia, Type 2 Diabetes 
Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease (NAFLD) 
Amendment:  
Protocol Amendment 3 
Date:   
 
21 March 2019 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled A 
Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Finding Study of ISIS 703802 
(ISIS 703802) Administered Subcutaneously to Subjects with Hypertriglyceridemia, Type 2 
Diabetes Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease (NAFLD) dated 21 March 
2019, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6R2) and with the moral, ethical and scientific principles governing 
clinical research as set out in the Declaration of Helsinki (Version 2013). 
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-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
21 March 2019 
 
6 
TABLE OF CONTENTS 
 
Page 
PROTOCOL SYNOPSIS ........................................................................................................... 12 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 19 
STUDY GLOSSARY .................................................................................................................. 20 
1.  
OBJECTIVES ................................................................................................................. 25 
1.1 
Primary Objective(s) ......................................................................................................25 
1.2 
Secondary Objective(s) ..................................................................................................25 
2. 
BACKGROUND AND RATIONALE .......................................................................... 25 
2.1 
Overview of Disease ......................................................................................................25 
2.2 
Therapeutic Rationale ....................................................................................................26 
2.3 
ISIS 703802 ...................................................................................................................27 
2.3.1 
Mechanism of Action .............................................................................................27 
2.3.2 
Chemistry ...............................................................................................................27 
2.3.3 
Preclinical Experience ............................................................................................28 
2.3.3.1 
Preclinical Pharmacology ................................................................................28 
2.3.3.2 
Preclinical Toxicology .....................................................................................29 
2.3.4 
Clinical Experience ................................................................................................30 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD ............................................................31 
2.4 
Rationale for Dose and Schedule of Administration .....................................................31 
2.5 
Benefit-Risk Assessment ...............................................................................................32 
2.5.1 
Benefit Assessment ................................................................................................32 
2.5.2 
Risk Assessment .....................................................................................................32 
2.5.3 
Overall Assessment of Benefit: Risk ......................................................................33 
3. 
EXPERIMENTAL PLAN .............................................................................................. 34 
3.1 
Study Design ..................................................................................................................34 
3.2 
Number of Study Centers ..............................................................................................35 
3.3 
Number of Subjects .......................................................................................................35 
3.4 
Overall Study Duration and Follow-up .........................................................................35 
3.4.1 
Screening ................................................................................................................35 
3.4.2 
Treatment ................................................................................................................35 
3.4.3 
Post-Treatment .......................................................................................................35 
3.5 
End-of-Study ..................................................................................................................36 
3.6 
Data and Safety Monitoring Board ................................................................................36 
4. 
SUBJECT ENROLLMENT ........................................................................................... 36 
4.1 
Screening .......................................................................................................................36 
4.2 
Randomization ...............................................................................................................36 
4.3 
Replacement of Subjects ................................................................................................36 
5. 
SUBJECT ELIGIBILITY .............................................................................................. 37 

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5.1 
Inclusion Criteria ...........................................................................................................37 
5.2 
Exclusion Criteria ..........................................................................................................38 
6. 
STUDY PROCEDURES ................................................................................................ 40 
6.1 
Study Schedule ..............................................................................................................40 
6.1.1 
Screening ................................................................................................................40 
6.1.2 
Treatment Period ....................................................................................................41 
6.1.3 
Post-Treatment Period ............................................................................................41 
6.2 
Study/Laboratory Assessments ......................................................................................41 
6.2.1 
Physical Exams and Vital Signs .............................................................................43 
6.2.2 
Electrocardiography ...............................................................................................43 
6.2.3 
PK Sampling ...........................................................................................................43 
6.3 
Restriction on the Lifestyle of Subjects .........................................................................43 
6.3.1 
Contraception Requirements ..................................................................................43 
6.3.2 
Other Requirements ................................................................................................44 
7. 
STUDY DRUG ................................................................................................................ 44 
7.1 
Study Drug Description .................................................................................................44 
7.1.1 
ISIS 703802 (ISIS 703802) ....................................................................................45 
7.1.2 
Placebo  ..................................................................................................................45 
7.2 
Packaging and Labeling .................................................................................................45 
7.3 
Study Drug Accountability ............................................................................................45 
8. 
TREATMENT OF SUBJECTS ..................................................................................... 45 
8.1 
Study Drug Administration ............................................................................................45 
8.2 
Other Protocol-Required Drugs .....................................................................................46 
8.3 
Other Protocol-Required Treatment Procedures ............................................................46 
8.4 
Treatment Precautions ...................................................................................................46 
8.5 
Safety Monitoring Rules ................................................................................................46 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................47 
8.5.2 
Safety Monitoring for Renal Function ...................................................................48 
8.5.3 
Safety Monitoring for Platelet Count Results ........................................................49 
8.5.4 
Safety Monitoring for Bleeding Events ..................................................................50 
8.5.5 
Safety Monitoring for Constitutional Symptoms ...................................................51 
8.5.6 
Safety Monitoring for Hypoglycemia ....................................................................51 
8.5.7 
Safety Monitoring for Documented Hyperglycemia ..............................................52 
8.6 
Stopping Rules ...............................................................................................................53 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................53 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................54 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................54 
8.6.4 
Stopping Rule for Documented Severe Hypoglycemia .........................................57 
8.7 
Adjustment of Dose and/or Treatment Schedule ...........................................................57 
8.8 
Discontinuation of Study Drug/Treatment ....................................................................57 

ISIS 703802-CS2 
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Amendment 3 
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21 March 2019 
 
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8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from Post-
Treatment Follow-up Period ..................................................................................58 
8.9 
Withdrawal of Subjects from the Study .........................................................................58 
8.10 
Concomitant Therapy and Procedures ...........................................................................58 
8.10.1 
Concomitant Therapy .............................................................................................59 
8.10.2 
Concomitant Procedures .........................................................................................59 
8.11 
Treatment Compliance ...................................................................................................59 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 60 
9.1 
Sponsor Review of Safety Information .........................................................................60 
9.2 
Regulatory Requirements ..............................................................................................60 
9.3 
Definitions .....................................................................................................................60 
9.3.1 
Adverse Event ........................................................................................................60 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................61 
9.3.3 
Serious Adverse Event (SAE) ................................................................................61 
9.4 
Monitoring and Recording of Adverse Events ..............................................................61 
9.4.1 
Serious Adverse Events ..........................................................................................61 
9.4.2 
Non-Serious Adverse Events ..................................................................................62 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................62 
9.4.3.1 
Relationship to the Study Drug ........................................................................62 
9.4.3.2 
Severity ............................................................................................................63 
9.4.3.3 
Action Taken with Study Drug ........................................................................63 
9.4.3.4 
Treatment Given for Adverse Event ................................................................63 
9.4.3.5 
Outcome of the Adverse Event ........................................................................63 
9.5 
Procedures for Handling Special Situations ..................................................................64 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................64 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............64 
9.5.3 
Dosing Errors .........................................................................................................65 
9.5.4 
Contraception and Pregnancy .................................................................................65 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 66 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................66 
10.1.1 
Primary Endpoint ...................................................................................................66 
10.1.2 
Secondary Endpoints ..............................................................................................66 
  
 
10.2 
Sample Size Considerations ...........................................................................................67 
10.3 
Populations .....................................................................................................................67 
10.4 
Definition of Baseline ....................................................................................................67 
10.5 
Interim Analysis .............................................................................................................67 
10.6 
Planned Methods of Analysis ........................................................................................68 
10.6.1 
Demographic and Baseline Characteristics ............................................................68 
10.6.2 
Safety Analysis .......................................................................................................68 

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10.6.2.1 Adverse Events ........................................................................................................68 
10.6.2.2 Clinical Laboratory Data ..........................................................................................68 
10.6.2.3 Vital Signs and Examinations ..................................................................................68 
10.6.3 
Efficacy Analysis ...................................................................................................69 
 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................70 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 71 
11.1 
Informed Consent ..........................................................................................................71 
11.2 
Ethical Conduct of the Study .........................................................................................71 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................71 
11.4 
Subject Confidentiality ..................................................................................................72 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 72 
12.1 
Protocol Amendments ....................................................................................................72 
12.2 
Study Termination .........................................................................................................72 
12.3 
Study Documentation and Storage ................................................................................73 
12.4 
Study Monitoring ...........................................................................................................73 
12.5 
Language ........................................................................................................................74 
12.6 
Compensation for Injury ................................................................................................74 
13. 
REFERENCES ................................................................................................................ 75 
14. 
APPENDICES ................................................................................................................. 78 
Appendix A 
Schedule of Procedures ....................................................................................78 
Appendix B 
List of Laboratory Analytes .............................................................................85 
Appendix C 
PK Sampling Schedule ....................................................................................87 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......90 
Appendix E 
Additional Laboratory Tests for Patients with Platelet Count <100,000/mm3 94 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ....................................................................................45 
Table 2 
Study Drug Dosing Information ............................................................................46 
Table 3 
Actions in Subjects with Low Platelet Count ........................................................56 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  (MOE-
Gapmer).  The sequence of ISIS 703802 is shown. ...............................................28 
 
 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
21 March 2019 
 
10 
 
PROTOCOL AMENDMENT  
Protocol Number:  
ISIS 703802-CS2 
Protocol Title:  
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Finding Study 
of ISIS 703802 (AKCEA-ANGPTL3-LRx) Administered Subcutaneously (SC) to 
Subjects with Hypertriglyceridemia, Type 2 Diabetes Mellitus (T2DM), and 
Nonalcoholic Fatty Liver Disease (NAFLD) 
Amendment Number:  Protocol Amendment 3 
Amendment Date:  
21 March 2019 
 
The following modifications to the Protocol ISIS 703802-CS2 Amendment 2 have been made. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design.  
The following table provides a summary list of major changes to the original protocol: 
Protocol Section 
Description of Change 
Rationale 
Title Pages 
Update the Sponsor Approval and 
Sponsor Medical Monitor to 
 
 MD. 
Change in Medical Monitor for the 
study 
Throughout (including Synopsis) 
Revise sample size for study to 96 
randomized. The new per Cohort 
sample size is 32 randomized. This 
results in 24 patients receiving 
active drug and 8 patients receiving 
placebo.  
Sponsor decision to revise sample 
size in order to accelerate further 
development for populations with 
serious hepatic steatosis. With the 
changes in sample size, the study 
remains adequately powered to 
provide the desired information on the 
primary objective and the key 
secondary objectives relevant to this 
population. 
Appendix A Schedule of 
Procedures – Weekly Dosing 
(Cohort A) 
Updated Cohort A Appendix A 
Footer H text to read: “During follow-
up period, hematology sampling for 
platelet values are taken every 14 
days (+/- 2 days) for 5 weeks after 
last dose of Study Drug, then at 
Week 8 and Week 13 Follow-up 
visits.” 
The intent of Cohort A Schedule of 
Procedures Footer H is to clarify that 
hematology samples for platelet 
values should continue to be taken 
every 14 days (+/- 2 days) after dosing 
stops. During the Treatment Period, 
Hematology samples are being drawn 
every two weeks starting at Week 1 
and continuing through W27/ET. It is 
important to note that even though 
Week 27 is the last Treatment Period 
visit, the last dose of IP is actually 
given at Week 26 for Cohort A. 
Therefore, bi-weekly hematology 
testing for platelet values should 
continue after dosing stops and taken 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 3 
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21 March 2019 
 
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Protocol Section 
Description of Change 
Rationale 
at the following visits: Follow-up Week 
2; which is actually 3 weeks post last 
dose), Follow-up Week 4; which is 
actually 5 weeks post last dose), then 
at Follow-up Week 8 and Follow-up 
Week 13. 
Appendix A Schedule of 
Procedures – Every 4-Week 
Dosing (Cohorts B & C) 
Updated Cohorts B & C Appendix A 
Footer H text to read: “Cohorts B & 
C Footer H: During the follow-up 
period, hematology sampling for 
platelet values should continue to be 
taken every 14 days (+/- 2 days) for 
6 weeks after Week 27/EOT, then at 
Week 4, Week 8 and Week 13 
Follow-up visits” 
To clarify the language used in Footer 
H of Appendix A Schedule of 
Procedures. As the Follow-Up Visits 
are already defined in the table, Footer 
H served as an aid to help explain the 
timing of the hematology samples 
when transitioning from Treatment 
Period to Follow-up period. 
Section 4.4 Unblinding of 
Treatment Assignment 
The Sponsor will be blinded 
throughout the study up until the last 
subject complets the treatment 
period.  
To provide more specific information 
on when the Sponsor will become 
unblinded.  
8.5.2 Safety Monitoring For Renal 
Function 
The following Lab alerts for 
abnormal renal tests were updated: 
• 
UACR > 165 mg/g 
• 
UPCR > 325 mg/g 
• 
New onset hematuria defined 
as ≥ 5 RBC/hpf (except for 
menstruating females) 
• 
Abnormal test results should 
now be repeated. 
• 
Supplemental renal tests should 
now be obtained within 7 days, 
and additional laboratory 
studies may be performed to 
identify if other potential 
etiologies may be casual factor 
• 
The 24-hour urine sample, urine 
albumin, and urine protein were 
removed from the supplemental 
rental tests. 
To align the renal monitoring criteria in 
this study with the criteria used in 
clinical studies of other anti-sense 
oligonucleotides conducted by the 
Sponsor  
8.6.2 Stopping Rules for Renal 
Function Test Results 
The following updates were made to 
8.6.2: 
• 
24-hour urine sample removed 
• 
eGFR criteria updated to: 
decrease of > 25% from 
baseline 
• 
Added criteria: 
o 
UACR > 165 mg/g 
o 
UPCR > 325 mg/g 
o 
New onset of hematuria 
(defined as ≥ 5 RBC/hpf) 
 
To align the renal stopping rules in this 
study with the rules used in clinical 
studies of other anti-sense 
oligonucleotides conducted by the 
Sponsor 
 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
21 March 2019 
 
12 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Finding Study of ISIS 
703802 (AKCEA-ANGPTL3-LRx) Administered Subcutaneously (SC) to Subjects with 
Hypertriglyceridemia, Type 2 Diabetes Mellitus (T2DM), and Nonalcoholic Fatty Liver 
Disease (NAFLD) 
Study Phase 
2 
Indication 
Subjects with Hypertriglyceridemia 
Primary Objective(s) 
To assess the effect of different doses and dosing regimens of ISIS 703802 on reduction 
in fasting triglycerides (TG) 
Secondary 
Objective(s) 
To evaluate the safety and tolerability of ISIS 703802  
To evaluate the effect of ISIS 703802 on changes from Baseline at End-of-Treatment on 
glucose and lipid metabolism, and liver fat 
To evaluate pharmacokinetics (PK) of ISIS 703802 across different doses and dose 
regimens 
To evaluate the effect of ISIS 703802 on changes from Baseline on biomarkers related to 
liver inflammation, adipokines and body composition 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 96 subjects will be randomized in a 3:1 ratio to receive ISIS 703802 or 
placebo.  The sample size was determined to provide statistical power for efficacy 
assessments.  Study Drug (ISIS 703802 or placebo) will be administered SC every week 
or every 4 weeks, depending on cohort assignment, for 26 weekly doses, or 6 doses 
every 4-weeks. 
Following end-of-treatment assessments, all subjects will then enter a 13-week 
post-treatment follow-up period. 
The primary safety and efficacy analysis time point is at Week 27 for subjects who 
received weekly dosing (Cohort A) and at Week 25 for subjects who received every 
4-week dosing (Cohorts B and C). 
Number of Subjects 
Approximately 96 
Study Population 
Inclusion Criteria 
1. 
Must have given written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all study 
requirements 
2. 
Males or females aged ≥ 18 and ≤ 70 years old at the time of informed consent 
3. 
Plasma TG at Screening > 150 mg/dL and at qualification of > 150 mg/dL 
4. 
Documented history of hepatic steatosis as determined by imaging (CT scan, 
MRI, FibroScan, or US) suggesting liver fat > 8%, or positive ultrasound at 
Screening  
5. 
Baseline MRI indicating hepatic fat fraction (HFF) > 8% 
6. 
Clinically confirmed diagnosis of T2DM 
a. 
Hemoglobin A1c > 6.5 and ≤ 10% at Screening 
b. 
On a stable dose of oral glucose-lowering medication (ie metformin, 
sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors) for at least 3 months 
before Screening and plan to remain on the same medication for the 
duration of the study 

ISIS 703802-CS2 
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Amendment 3 
Protocol 
 
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7. 
Body mass index between 27- 40 kg/m2, inclusive, at Screening  
8. 
If taking lipid lowering medication, subjects must be on a stable dose for at least 
3 months before first dose of study drug and plan to remain on the same 
medication for the duration of the study 
9. 
Females:  must be non-pregnant and non-lactating and either;  
a. 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy); 
b. 
post-menopausal (defined as 12 months of spontaneous amenorrhea in 
females > 55 years of age or, in females ≤ 55 years, 12 months of 
spontaneous amenorrhea without an alternative medical cause and FSH 
levels in the postmenopausal range for the laboratory involved); 
c. 
Abstinent* or; 
d. 
if engaged in sexual relations of child-bearing potential, agree to use 2 
highly effective contraceptive methods (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 (ISIS 703802 or placebo) 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with 
the preferred and usual lifestyle of the subject.  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 
10. Males must be surgically sterile or, if engaged in sexual relations with a female of 
child-bearing potential, the subject must be using 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 ISIS 703802 
Exclusion Criteria 
1. 
Type 1 diabetes mellitus 
2. 
Active chronic liver disease, alcoholic liver disease, Wilson’s disease 
hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, genetic 
hemochromatosis, known or suspected hepatocellular carcinoma, history of or 
planned liver transplant for end-stage liver disease of any etiology 
3. 
Documented history of advanced liver fibrosis  
4. 
History of cirrhosis and/or hepatic decompensation including ascites, hepatic 
encephalopathy, or variceal bleeding 
5. 
Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 
6. 
History of acute kidney injury within 12 months of Screening 
7. 
Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
8. 
Subjects with a history of major bleed or high-risk of bleeding diathesis 
9. 
Clinically-significant abnormalities in screening laboratory values that would render 
a subject unsuitable for inclusion, including the following: 
a. 
Positive test (including trace) for blood on urinalysis.  In the event of a 
positive test, eligibility may be confirmed with urine microscopy showing ≤ 5 
red blood cells per high power field 

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14 
b. 
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 ˂ 300 mg/24-hr 
c. 
Estimated GFR ˂ 60 mL/min/1.73 m2 (as determined by the Chronic Kidney 
Disease-Epidemiological Collaboration (CKD-EPI) Equation)  
d. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x 
ULN 
e. 
Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s 
syndrome in which case total bilirubin must be ≤ 3 mg/dL 
f. 
Alkaline phosphatase (ALP) > 1.5 x ULN 
g. 
Platelet count ˂ LLN 
10. Known history of or positive test for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B 
11. Uncontrolled hyper- or hypothyroidism. Subjects on dose stable replacement 
therapy for at least 3 months prior to Screening will be allowed 
12. History of clinically significant acute cardiac event within 6 months before 
Screening (includes stroke, transient ischemic attack, and coronary heart disease 
[angina pectoris, myocardial infarction, revascularization procedures])  
13. History of heart failure with NYHA greater than Class II 
14. Current acute or chronic inflammatory disease 
15. Hypersensitivity to the active substance or to any of the excipients 
16. Active untreated mental disorder or depression. Subjects who are on a stable 
dose of medication (excluding atypical antipsychotics) for at least 6 months before 
screening and whose treating physicians consider them to be mentally stable may 
be enrolled  
17. Any major surgery including bariatric surgery within 3 months of Screening 
18. Weight change > 5% within 3 months before Screening or during diet run in 
period 
19. Currently taking parenteral or chronic oral corticosteroids, amiodarone, tamoxifen, 
obeticholic acid, atypical antipsychotics, HIV protease inhibitors, or 
ursodeoxycholic acid 
20. Alcohol consumption > 21 units of alcohol per week for men and > 14 units of 
alcohol per week for women over a two-year time frame prior to the Baseline MRI 
eligibility (One drink "unit" or one standard drink is equivalent to a 12 ounce beer, 
a 4 ounce glass of wine, or a 1 ounce shot of hard liquor)  
21. 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 
22. Use of warfarin or other coumarins, direct thrombin inhibitors or Factor Xa 
inhibitors 
23. Use of anti-platelet therapies unless the dose has been stable for 4 weeks prior 
to the first dose of ANGPTL3-LRx and will remain on a stable regimen through the 
end of the Post-Treatment Follow-up Period, during which regular clinical 
monitoring will be performed 
24. Use of insulin or insulin analogs, GLP-1 agonists, and PPARᵞ agonists 
(pioglitazone or rosiglitazone)  
25. Treatment with another investigational drug, biological agent, or device within 
1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
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26. Treatment with any non-Akcea/non-Ionis oligonucleotide (including small 
interfering ribonucleic acid [siRNA]) at any time or prior treatment with an Ionis 
oligonucleotide or siRNA within 9 months of Screening.  Subjects that have 
previously received only 1 dose of an Ionis oligonucleotide as part of a clinical 
study may be included as long as ≥ 4 months have elapsed since dosing 
27. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
28. Unwillingness to comply with study procedures, including follow-up, as specified 
by this protocol, or unwillingness to cooperate fully with the Investigator 
29. Subjects with conditions contraindicated for MRI procedures including subjects 
who have any metal implant (e.g., heart pacemaker, rods, screws, aneurysm 
clips) that contraindicates MRI procedures 
30. Have any other conditions, which, in the opinion of the Investigator or Sponsor 
would make the subject unsuitable for inclusion, or could interfere with the 
subject participating in or completing the study 
Treatment Groups  
Subjects will be randomized to 3 parallel cohorts: 
Cohort A (n = 32): Subjects will be randomized 3:1 to receive 20 mg ISIS 703802 or 
placebo SC once every week for 26 doses. 
Cohort B (n = 32): Subjects will be randomized 3:1 to receive 40 mg ISIS 703802 or 
placebo SC once every 4 weeks for 6 doses. 
Cohort C (n = 32): Subjects will be randomized 3:1 to receive 80 mg ISIS 703802 or 
placebo SC once every 4 weeks for 6 doses. 
Cohort 
Treatment 
# Doses 
Total Study Drug  
A 
20 mg ISIS 703802 or placebo 
(Every week) 
26 
520 mg 
B 
40 mg ISIS 703802 or placebo 
(Every 4 weeks) 
6 
240 mg 
C 
80 mg ISIS 703802 or placebo  
(Every 4 weeks) 
6 
480 mg 
Study Drug Dosage 
and Administration 
The Sponsor will provide ISIS 703802 in a single use vial with a concentration of 100 
mg/mL and matching volume placebo: 
Cohort A: 20 mg every week of ISIS 703802 or placebo (0.2 mL)  
Cohort B: 40 mg every 4 weeks of ISIS 703802 or placebo (0.4 mL) 
Cohort C: 80 mg every 4 weeks of ISIS 703802 or placebo (0.8 mL) 
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 
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 parameters.  The range of dosing proposed for the 
present study will provide the equivalent drug exposure of 10 mg (from 40 mg monthly), 
and 20 mg (from 20 mg weekly and 80 mg monthly) administered weekly, and is 
predicted (based on modelling of PK/PD data obtained in Phase 1 study) to result in 
mean reductions from Baseline in TGs ranging from approximately 45 to 55% at 
steady-state. 
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.  

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Study Visit Schedule 
and Procedures 
Detailed information regarding the study procedures are outlined in Section 6, 
Appendices A and C. 
All subjects enrolled will be randomized to 6 months of treatment in 1 of 3 treatment 
cohorts.  
The study for an individual subject will generally consist of the following periods:  
• 
A Screening Period (up to 5 weeks), including a 4-week diet stabilization phase, 
where appropriate  
• 
A Treatment Period (26 weeks) during which Study Drug will be administered 
per assigned cohort by SC injection 
• 
A Post-treatment Follow-up Period (13 weeks) 
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 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 
stabilization phase. At the qualification visit TGs will be measured. MRI 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 TG and MRI, 
defined as having greater than 8% liver fat assessed by MRI-PDFF (via central reviewer) 
will return to the clinic on Day 1. TG and MRI results must be available prior to 
randomization and administration of the first dose of study drug. 
Subjects assigned to Cohort A will receive a single SC dose of ISIS 703802 or placebo 
every week for a total of 26 doses.  Subjects assigned to Cohorts B and C will receive a 
single SC dose of ISIS 703802 or placebo every 4 weeks for a total of 6 doses.  Subjects 
will return regularly for outpatient visits throughout the treatment period according to the 
Schedule of Procedures (Appendix A). 
Following the end of the treatment period, 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 schedules. 
Safety and Tolerability 
Evaluations 
Safety and tolerability assessments include: adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, ECGs and use of concomitant 
medications.   
Safety and tolerability results in patients dosed with ISIS 703802 will be compared with 
those dosed with placebo. 

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Efficacy and Safety 
Evaluations 
The primary analysis time point is at Week 27 for subjects who received every week 
dosing (Cohort A) and Week 25 for subjects who received every 4-week dosing (Cohorts 
B and C). 
Primary endpoint:  
• 
Percent change in fasting TG level from Baseline at the primary analysis time 
point  
Secondary endpoints: Evaluate the effect of ISIS 703802 on changes from Baseline at 
the primary analysis timepoint in:  
• 
Absolute and percentage change in ANGPTL3 protein, TC, LDL-C, HDL-C, 
VLDL-C, Non-HDL-C, ApoB (ApoB-48, ApoB-100), ApoCIII, ApoAI, FFA, Lp(a) 
• 
Absolute change in fasting plasma glucose, HbA1c, fasting insulin HOMA-IR, 
fructosamine and glycated albumin 
• 
Absolute and percent change in weight, SBP and DBP 
• 
Absolute and percent change in hepatic fat fraction (HFF) by MRI-PDFF 
• 
Proportion of subjects reaching hepatic fat fraction (HFF) ≤ 8% by MRI-PDFF 
• 
Absolute change in Fatty Liver Index (FLI) 
• 
Absolute change in ALT and AST 
• 
Adipokines and related metabolic markers such as leptin, adiponectin, 
phospholipids (e.g. ceramides, sphingolipids, diacylglycerol) 
• 
Body composition as measured by single slice MRI of subcutaneous adipose 
tissue (SAT) and visceral adipose tissue (VAT), waist circumference, WHR 
(waist-to-hip ratio), and BMI 
 
 
 
Pharmacokinetic 
Evaluations 
Plasma samples will be taken from all subjects for the measurement of ISIS 703802 
plasma trough levels throughout treatment and during the post-treatment follow-up period. 
Plasma sample collection time points are detailed in Appendix A and C.  In addition, in a 
subset of subjects (approximately 12 subjects per cohort), more frequent plasma samples 
will be taken following the first administration and Day 176 (for Cohort A) or Day 141 (for 
Cohorts B and C) dose to determine PK parameters.  Plasma sample collection time 
points are detailed in Appendix A and C. 
The plasma ISIS 703802 levels over time will be descriptively summarized by treatment 
with stratification by subject immunogenicity status, if applicable.  Apparent terminal 
elimination half-life will be calculated in subjects who received ISIS 703802 treatment 
using a non-compartmental method, if data permitted. 
In addition, Cmax, Tmax, and AUC values will be calculated for the PK subgroup. PK 
parameters will be descriptively summarized by treatment with stratification by subject 
immunogenicity status. 

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Statistical 
Considerations 
The primary efficacy analysis for the primary endpoint will be the pairwise comparison of 
percent change from Baseline to the primary analysis time point in fasting TG between 
ISIS 703802 treated groups and placebo group in the Full Analysis Set. 
The data will be analyzed using an ANCOVA model with the Baseline TG level as a 
covariate. 
Dose selection for the further development will be based on the following efficacy and 
safety considerations; more than 1 dose may meet these criteria.  An effective dose, or 
dose regimen, will be one that achieves a clinically-meaningful reduction in plasma TG 
levels.  Safety will be evaluated on the basis of incidence of expected and unexpected 
treatment-related SAEs, and other specific safety considerations including the incidence 
of platelet reductions. 
Sample Size Considerations: 
Subjects in the placebo arm will be pooled for the statistical analysis in order to compare 
active and control arms. Therefore, each of the 4 arms will have 24 patients. Considering 
10% dropouts, 21 patients per group are expected to complete the study. 
A sample size of 21 patients per arm will be able to detect: 
• 
A treatment difference in mean triglycerides of 50% based on a between-patient 
standard deviation of 46% (Jani et al. 2014)  and a two-sample t-test with an 
unadjusted alpha level of 0.05 with 93% power. 
• 
A treatment difference in mean liver fat of 4.75% based on a between-patient 
standard deviation of 3.96% (Tiikkainen et al. 2004) and a two-sample t-test with an 
unadjusted alpha level of 0.05 with 96% power. 
Sponsor/Collaborator 
Akcea Therapeutics, Inc./Ionis Pharmaceuticals, Inc. 
 
 

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STUDY DESIGN AND TREATMENT SCHEMA 
 
SCREENING PERIOD 
Weeks -5 to 0 
TREATMENT PERIOD 
Weeks 1 to 21/26* 
Dosing per assigned cohort: 
Cohort A: (n = 32):  20 mg ISIS 703802or placebo 
SC once every week for 26 doses. 
Cohort B:  (n = 32): 40 mg ISIS 703802 or placebo 
SC once every 4 weeks for 6 doses.  
Cohort C:  (n = 32): 80 mg ISIS 703802 or placebo 
SC once every 4 weeks for 6 doses.  
Routine safety assessments:  PK and PD/efficacy 
assessments at specified time points 
* The primary analysis time point  is at Week 27 
for patients who received every week dosing 
(Cohort A) and Week 25 for patients who received 
every 4-week dosing (Cohorts B and C). 
POST-TREATMENT 
EVALUATIONS 
3 clinical visits for safety, efficacy,  
PK and PD assessments 
Cohort A - Weeks 4, 8 and 13 after 
last dose of Study Drug 
Cohorts B & C - Weeks 6, 8 and 13 
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 
assessments 
END-OF-STUDY 
PROCEDURES 
Early Termination or 3rd Follow-
Up visit (13 Weeks after end of 
treatment period) 

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STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AE 
adverse event 
ISIS 703802 
Antisense inhibitor of ANGPTL3 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANA 
antinuclear antibody 
ANCOVA 
Analysis of Covariance 
ANGPTL3 
Angiopoietin like 3 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
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 
Base pair 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Centigrade 
C5a 
complement Factor C5a (activated complement split 
product) 
Cmax 
maximum concentration 
CBC 
complete blood count 
CL 
systemic clearance 
CMV 
Cytomegalovirus 
CRF 
case report form 
CRP 
C-reactive protein 
CS 
clinically significant 
CT 
computed tomography 

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Abbreviation 
Definition 
CTCAE 
Common Terminology Criteria for Adverse Events  
CVD 
Cardio Vascular Disease 
dL 
Deciliter 
DLT 
dose-limiting toxicity 
DSMB 
Data And Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EDC 
electronic data capture 
ESR 
erythrocyte sedimentation rate 
FHBL2 
Familial Combined Hypolipidemia 
FLI 
Fatty Liver Index 
g 
Gram 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HAV 
hepatitis A virus 
Hb 
Hemoglobin 
HBsAg 
hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
hepatitis C virus 
HDL-C 
High density lipoprotein cholesterol 
HFF 
Hepatic Fat Fraction 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HOMA-IR 
Homeostatic Model Assessment Insulin Resistance 
HR 
heart rate 
hr, hrs 
hour(s) 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 

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Abbreviation 
Definition 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon-gamma 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1 beta 
IL-1RA 
interleukin-1 receptor antagonist 
IL-6 
interleukin-6 
IL-8 
interleukin-8 
IL-10 
interleukin-10 
IL-12 
interleukin-12 
IL-12p40p70 
interleukin-12 p40 (40 kDa) and p70 (70 kDa) subunits  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 703802 
antisense inhibitor of ANGPTL3 
IV 
Intravenous(ly) 
IXRS 
Interactive voice/internet response system 
kg 
Kilogram 
L 
Liter 
LDH 
lactate dehydrogenase 
LDL-C 
Low Density Lipoprotein Cholesterol 
LDLR 
Low Density Lipoprotein Receptor 
Lp(a) 
Lipoprotein (a) 
LVEF 
left ventricular ejection fraction 
m2 
square meter 
MAD 
multiple ascending dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
mg 
milligram 

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Abbreviation 
Definition 
min 
minute 
mL 
milliliter 
mm 
millimeter 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
NAFLD 
Non Alcoholic Fatty Liver Disease 
NASH 
Non Alcoholic Steatohepatitis 
NCS 
not clinically significant 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
on study 
The patient is ‘on study’ from signing of the informed consent 
until their last study visit 
OTC 
Over the Counter 
PC 
personal computer 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
pRBC 
packed red blood cells 
PT 
prothrombin time 
QoL 
quality of life 
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) 
sTNF-R1 
soluble tumor necrosis Factor receptor 1 
Study Day 1 
defined as the first day Study Drug product is administered 
to the patient 

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Abbreviation 
Definition 
Study Drug 
ISIS 703802 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximal concentration 
TC 
Total Cholesterol 
TG 
Triglyceride 
TNF-α 
tumor necrosis Factor-alpha 
TNFR 
tumor necrosis factor receptor 
TNF-RI 
tumor necrosis factor receptor I 
TNF-RII 
tumor necrosis factor receptor II 
UACR 
Urine Albumin Creatinine Ratio 
ULN 
upper limit of normal 
UPCR 
Urine Protein Creatinine Ratio 
US 
Ultrasound 
VAT 
Visceral Adipose Tissue 
VLDL-C 
Very Low Density 
WBC 
white blood cell 
WHO 
World Health Organization 
WHR 
Waist Hip Ratio 
WMA 
World Medical Association 
 
 
 

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1.  
OBJECTIVES 
1.1 
Primary Objective(s) 
To assess the effect of different doses and dosing regimens of ISIS 703802 on reduction in 
fasting triglycerides (TG). 
1.2 
Secondary Objective(s) 
To evaluate the safety and tolerability of ISIS 703802.  
To evaluate the effect of ISIS 703802 on changes from Baseline at End-of-Treatment on glucose 
and lipid metabolism, and liver fat. 
To evaluate the pharmacokinetics (PK) of ISIS 703802 across different doses and dose regimens. 
To evaluate the effect of ISIS 703802 on changes from Baseline on biomarkers related to liver 
inflammation, adipokines, and body composition. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Hypertriglyceridemia commonly observed in diabetic dyslipidemia is generally due to hepatic 
over production of triglyceride-rich very-low-density lipoprotein (VLDL) particles as well as 
impaired intravascular catabolism as a result of decreased lipoprotein lipase activity (Adiels et al. 
2008). Its etiology includes primary factors (i.e., genetic causes, such as a mutation in a receptor 
protein). Secondary causes of hypertriglyceridemia are far more common and include metabolic 
syndrome/insulin resistance, obesity, physical inactivity, cigarette smoking, excess alcohol and a 
diet very high in carbohydrates. The guidelines from both the National Cholesterol Education 
Program Adult Treatment Panel III (NCEP 2002) and the American Diabetes Association (ADA 
2008) recommend a target TG level of less than 150 mg/dL to reduce cardiovascular risk based 
on evidence from clinical studies demonstrating that elevated TG levels are an independent risk 
factor for atherosclerotic CVD.  
Hypertriglyceridemia associated with insulin resistance and obesity commonly presents with 
Type 2 diabetes mellitus (T2DM) which affects more than a third of a billion people worldwide 
and is the leading cause of cardiovascular disease, with estimated annual worldwide health care 
costs exceeding half a trillion dollars (Dake et al. 2016). Dyslipidemia in individuals with type 2 
diabetes is very common and a major contributing factor to the development of atherosclerosis.  
The phenotype of dyslipidemia in patients with diabetes is that of elevated triglycerides 
(hypertriglyceridemia), reduced HDL-C, smaller LDL particles, but with relatively similar 
LDL-C levels compared with the general population.  
The association of diabetic dyslipidemia, insulin resistance, and excess lipid storage in the form 
of visceral obesity and hepatic steatosis has long been recognized (Shulman 2014). Hepatic 
steatosis also known as non-alcoholic fatty liver disease (NAFLD) results from increased hepatic 
uptake of free fatty acids derived mainly from the hydrolysis of adipose-tissue triglycerides 
(increased because of insulin resistance) but also from dietary chylomicrons overload and hepatic 
lipogenesis.  Insulin resistance is one of the key pathogenic factors in the development and 

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progression of non-alcoholic fatty liver disease and also plays a major role in the development of 
the metabolic syndrome and cardiovascular disease (Targher et al. 2010). Worldwide prevalence 
of NAFLD/NASH is reported to range from 6.3% to 33% with a median of 20% in the general 
population. The estimated prevalence of NASH is lower, ranging from 3 to 5 % (Vernon et al. 
2011).  In one study the prevalence of NAFLD in high-risk groups such as in T2DM with 
dyslipidemia was estimated to be as high as 69% (Leite et al. 2009) which was higher than the 
50% prevalence reported in patients with dyslipidemia with or without diabetes who attended 
lipid clinics  (Assy et al. 2000). Despite the high prevalence, there are currently no approved 
pharmacological therapies for NAFLD associated with dyslipidemia in diabetic patients, 
highlighting the urgent need to develop effective therapeutic strategies for this common 
condition. 
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 the liver, where its expression is downregulated by 
leptin and insulin (Inukai et al. 2004). Hepatic specific knock-down of ANGPTL3 mRNA is 
associated with a 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 (AKCEA-ANGPTL3-LRx) 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.  

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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 the 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. 2008). 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 the 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 

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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, has been studied 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 
2ʹ-MOE 
2ʹ-MOE 
2ʹ-Deoxy 
GalNAc = THA-GalNAc cluster 
2ʹ-MOE = 2ʹ-methoxyethyl RNA 
2ʹ-Deoxy = DNA 
s = phosphorothioate linkage 
o = phosphodiester linkage 
(RNase H1 sensitive) 
GalNAc 
GsGoAoCoAo 
TsTsGsCsCsAsGsTsAsAs 
ToCoGsCsA 

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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 
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 

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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 monkey 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 
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 

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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 an 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 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 range of dosing proposed for the present study will 
provide the equivalent drug exposure of 10 mg (from 40 mg monthly), and 20 mg (from 20 mg 
weekly and 80 mg monthly) administered weekly, and is predicted (based on modelling of 
PK/PD data obtained in Phase 1 study) to result in mean reductions from Baseline in TGs 
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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.    
Preclinical pharmacology experiments in Tg-mice and non-human primates demonstrated that 
ISIS 703802 achieved an equivalent reduction in ANGPTL3 plasma concentration to that of the 
unconjugated form, at 1/10th of the unconjugated ASO (ISIS 563580) dose.   
2.5 
Benefit-Risk Assessment 
2.5.1 
Benefit Assessment 
The current study is designed to evaluate the safety and tolerance of ISIS 703802 in patients with 
hypertriglyceridemia, Type 2 Diabetes Mellitus (T2DM) and Nonalcoholic Fatty Liver Disease 
(NAFLD). The dose selected is expected to reduce ANGPTL3 and result in a reduction of 
triglyceride levels, reduction of fat content of the liver and improvement of glycemic control in 
T2DM patients. 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 patients 
with hypertriglyceridemia, T2DM and, NAFLD.  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 
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. 
• One subject in the 60 mg weekly dose cohort had an approximately 5 x ULN increase of 
ALT, without increase in bilirubin, which was considered a treatment related adverse 
event (AE) by Principal Investigator (PI) 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. There were no other observed clinically significant changes in ALT 
and liver function in an ongoing 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 

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effects observed following SC administration of 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 a 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% in the Phase 1 study in healthy volunteers.  The objective of this study is to assess the 
effect of TG lowering in these subjects. 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 subjects with high TG levels and T2DM. 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 hypertriglyceridemia, dyslipidemia, NAFLD and associated metabolic complications and 
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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 (see Section 8.5 Safety Monitoring Rules). 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 96 subjects will be randomized in a 3:1 ratio to receive ISIS 703802 or placebo.  
The sample size was determined to provide statistical power for efficacy assessments. Study 
Drug (ISIS 703802 or placebo) will be administered SC every week or every 4 weeks, depending 
on cohort assignment, for 26 weekly doses, or 6 every 4-week doses. 
Subjects will be evaluated for study eligibility during Screening and Qualification, which takes 
place up to 5 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 a 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 (≥ 150 mg/dL).   MRI 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 
greater than 8% liver fat assessed by MRI-PDFF (via central reviewer) will return to the clinic on 
Day 1. TG and MRI results must be available prior to randomization and administration of the 
first dose of Study Drug. Subjects who continue to meet all eligibility criteria at Day 1 will be 
randomized to 1 of the 3 dosing cohorts, with each cohort having a 3:1 ratio to receive ISIS 
703802 or matching volume of placebo, respectively, by SC injection. 
The primary safety and efficacy analysis time point is at Week 27 for subjects who received 
weekly dosing (Cohort A) and at Week 25 for subjects who received every 4-week dosing 
(Cohorts B and C).  
Cohort A (n = 32): 20 mg ISIS 703802 or placebo (3:1) SC once every week for 26 doses. 
Cohort B (n = 32): 40 mg ISIS 703802 or placebo SC (3:1) once every 4 weeks for 6 doses. 
Cohort C (n = 32): 80 mg ISIS 703802 or placebo SC (3:1) once every 4 weeks for 6 doses. 
Subjects will return regularly for outpatient visits throughout the treatment period according to 
the Schedule of Procedures (Appendix A). 
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).  

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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. 
3.2 
Number of Study Centers 
This is a multicenter, multinational study. 
3.3 
Number of Subjects 
Approximately 96 subjects are planned to be enrolled in this study.   
Approximately 32 subjects will be assigned to each cohort, with 24 subjects receiving ISIS 
703802 and 8 receiving placebo.  
3.4 
Overall Study Duration and Follow-up 
The length of subjects’ participation in the study will be up to 44 weeks, including an up to 
5-week Screening Period, that includes a 4-week diet stabilization/run-in period for subjects not 
already on a stable diet, and a 1-week qualification period, a 26-week treatment period, and a 
13-week post-treatment evaluation period. Please refer to the Schedule of Procedures in 
Appendix A.  
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 
Subject eligibility for the study will be determined within 35 days/5 weeks prior to 
randomization. Potential subjects will report to the Study Center for screening/qualification 
assessments at specified intervals within the 5-week Screening Period as detailed in the Schedule 
of Procedures in Appendix A. 
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, if applicable. Subsequent 
administrations of Study Drug may occur at home or at 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 
After the dosing with Study Drug is completed, subjects will then enter the 13-week 
post-treatment follow-up period and will return to the Study Center for 3 follow-up visits 
according to the Schedule of Procedures in Appendix A.   
The final study visit for each subject will be 13 weeks after the Treatment Period (last dose 
through one dosing interval post last dose). 

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3.5 
End-of-Study 
The End-of-Study is defined as the last subject’s last visit. 
3.6 
Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board (DSMB) will be assembled to review safety, 
tolerability and efficacy (as needed) data collected on ISIS 703802 during this study.  Based on 
its ongoing assessment of the safety and tolerability of ISIS 703802, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping or continuing the study as planned.  
Details on the safety assessments, frequency of review, meeting schedules and controlled access 
to unblinded data are outlined in the DSMB Charter and Statistical Analysis Plan (SAP).   
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. 
Subjects must sign the informed consent form before any screening tests or assessments are 
performed. At the time of consent, the subject will be assigned a unique screening 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. At the time of randomization, subjects will be assigned a unique randomization 
number. The subject identification number must remain constant throughout the entire trial.  
Subject identification numbers and randomization numbers, once assigned, will not be reused. 
4.2 
Randomization 
Subjects will be randomized after all screening and qualification assessments have been 
completed and after the Investigator has verified that they are eligible per criteria in Sections 5.1 
and 5.2. No subject may begin treatment prior to randomization and assignment of a unique 
subject identification number. 
Using an Interactive Web-Response System (IXRS), eligible subjects will be randomized in a 
1:1:1 ratio to 1 of the 3 parallel-dose cohorts (Cohorts A, B, or C). Within each dose cohort, 
subjects will be randomized in a 3:1 ratio to receive ISIS 703802 or matching volume of placebo, 
respectively. 
A permuted block schedule will be used. The randomization schedule will be generated and held 
by an independent vendor. 
4.3 
Replacement of Subjects 
Subjects who withdraw from the study will not be replaced. 

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4.4 
Unblinding of Treatment Assignment 
All subjects, monitors, and Study Center personnel related to the study will be blinded 
throughout the study and until all subjects have completed the study and the database has been 
locked. The Sponsor will be blinded throughout the study and until all subjects have completed 
the treatment period.  However, if a subject has suffered a SAE (as defined in Section 9.3.3), 
and/or when knowledge of the treatment assignment will impact the clinical management of the 
subject, the Investigator will have the ability to unblind the treatment assignment for that subject 
using the IXRS. The Sponsor will determine the point at which all treatment assignments will be 
unblinded. The Sponsor or designee will be informed of the unblinding of a subject within 
24 hours. In addition, all SUSARs will be unblinded by the Sponsor’s or designee’s Drug Safety 
and Quality Assurance personnel for the purpose of regulatory reporting (see Section 9.2). 
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 5 weeks of Study Day 1 or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements 
2. Males or females aged ≥ 18 and ≤ 70 years old at the time of informed consent 
3. Plasma TG at Screening > 150 mg/dL and at qualification of > 150 mg/dL 
4. Documented history of hepatic steatosis as determined by at least one imaging record 
(CT scan, MRI, FibroScan, or US) suggesting liver fat > 8%, or positive ultrasound at 
Screening  
5. Baseline MRI indicating hepatic fat fraction (HFF) > 8% 
6. Clinically confirmed diagnosis of T2DM 
a. Hemoglobin A1c > 6.5 and ≤ 10% at Screening 
b. On a stable dose of oral glucose-lowering medication (i.e. metformin, sulfonylureas, 
DPP-4 inhibitors, SGLT2 inhibitors) for at least 3 months before Screening and plan 
to remain on the same medication for the duration of the study 
7. Body mass index between 27- 40 kg/m2, inclusive, at Screening  
8. If taking lipid lowering medication, subjects must be on a stable dose for at least 
3 months before first dose of Study Drug and plan to remain on the same medication for 
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9. Females:  must be non-pregnant and non-lactating and either;  
a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) or; 
b. post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and FSH levels in the postmenopausal range for 
the laboratory involved) or; 
c. Abstinent* or; 
d. if engaged in sexual relations of child-bearing potential, agree to use 2 highly 
effective contraceptive methods (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 (ISIS 
703802 or placebo) 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the subject. 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 
10. Males must be surgically sterile or, if engaged in sexual relations with a female of 
child-bearing potential, the subject must be using 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 ISIS 703802 
5.2 
Exclusion Criteria 
1. Type 1 diabetes mellitus 
2. Active chronic liver disease, alcoholic liver disease, Wilson’s disease hemochromatosis, 
primary biliary cirrhosis, primary sclerosing cholangitis, genetic hemochromatosis, 
known or suspected hepatocellular carcinoma, history of or planned liver transplant for 
end-stage liver disease of any etiology 
3. Documented history of advanced liver fibrosis  
4. History of cirrhosis and/or hepatic decompensation including ascites, hepatic 
encephalopathy, or variceal bleeding 
5. Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 
6. History of acute kidney injury within 12 months of Screening 
7. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
8. Subjects with a history of major bleed or high-risk of bleeding diathesis 
9. Clinically-significant abnormalities in screening laboratory values that would render a 
subject unsuitable for inclusion, including the following: 

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a. Positive test (including trace) for blood on urinalysis.  In the event of a positive test, 
eligibility may be confirmed with urine microscopy showing ≤ 5 red blood cells per 
high power field 
b. 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 ˂ 300 mg/24-hr 
c. Estimated GFR ˂ 60 mL/min/1.73 m2 (as determined by the Chronic Kidney 
Disease-Epidemiological Collaboration (CKD-EPI) Equation)  
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN 
e. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in 
which case total bilirubin must be ≤ 3 mg/dL 
f. Alkaline phosphatase (ALP) > 1.5 x ULN 
g. Platelet count ˂ LLN 
10. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
11. Uncontrolled hyper- or hypothyroidism. Subjects on dose stable replacement therapy for 
at least 3 months prior to Screening will be allowed 
12. History of clinically significant acute cardiac event within 6 months before Screening 
(includes stroke, transient ischemic attack, and coronary heart disease [angina pectoris, 
myocardial infarction, revascularization procedures])  
13. History of heart failure with NYHA greater than Class II 
14. Current acute or chronic inflammatory disease 
15. Hypersensitivity to the active substance or to any of the excipients 
16. Active untreated mental disorder or depression. Subjects who are on a stable dose of 
medication (excluding atypical antipsychotics) for at least 6 months before Screening and 
whose treating physicians consider them to be mentally stable may be enrolled  
17. Any major surgery including bariatric surgery within 3 months of Screening 
18. Weight change > 5% within 3 months before Screening or during diet run in period 
19. Currently taking parenteral or chronic oral corticosteroids, amiodarone, tamoxifen, 
obeticholic acid, atypical antipsychotics, HIV protease inhibitors, or ursodeoxycholic 
acid 
20. Alcohol consumption > 21 units of alcohol per week for men and > 14 units of alcohol 
per week for women over a two year time frame prior to the Baseline MRI eligibility 
(One drink "unit" or one standard drink is equivalent to a 12 ounce beer, a 4 ounce glass 
of wine, or a 1 ounce shot of hard liquor)  
21. 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 
22. Use of warfarin or other coumarins, direct thrombin inhibitors or Factor Xa inhibitors 

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23. Use of anti-platelet therapies unless the dose has been stable for 4 weeks prior to the first 
dose of ANGPTL3-LRx and will remain on a stable regimen through the end of the Post-
Treatment Follow-up Period, during which regular clinical monitoring will be performed 
24. Use of Insulin or insulin analogs, GLP-1 agonists, and PPARᵞ agonists (pioglitazone or 
rosiglitazone)  
25. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
26. Treatment with any non-Akcea/non-Ionis oligonucleotide (including small interfering 
ribonucleic acid [siRNA]) at any time or prior treatment with an Ionis oligonucleotide or 
siRNA within 9 months of Screening.  Subjects that have previously received only 1 dose 
of an Ionis oligonucleotide as part of a clinical study may be included as long as 
≥ 4 months have elapsed since dosing 
27. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
28. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
29. Subjects with conditions contraindicated for MRI procedures including subjects who 
have any metal implant (e.g., heart pacemaker, rods, screws, aneurysm clips) that 
contraindicates MRI procedures. 
30. Have any other conditions, which, in the opinion of the Investigator or Sponsor would 
make the subject unsuitable for inclusion, or could interfere with the subject 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 
Written informed consent for the study will be obtained prior to the performance of any study-
related procedures including screening procedures. An up to 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, including collection of race and ethnicity, 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 retested for determination of subject eligibility after consultation with the Sponsor 
Medical Monitor. 

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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 will be obtained during screening once all other eligibility criteria are met to 
assess liver fat content.   
On confirmation of eligibility and prior to randomization, subjects will also undergo a 24 hr 
urine collection for creatinine, albumin, and protein as a Qualification assessment. 
6.1.2 Treatment Period 
During the treatment period, eligible subjects will be randomized and report to the Study Center 
for clinic visits. Subjects will be randomized to 1 of 3 dose cohorts and receive 20 mg doses of 
Study Drug administered by SC injection once per week (weekly) for 26 weeks in Cohort A, 
40 mg doses of Study Drug administered by SC injection once every 4 weeks for 21 weeks in 
Cohort B, and 80 mg doses of Study Drug administered by SC injection once every 4 weeks for 
21 weeks in Cohort C (Section 8.1). 
Collection and measurement of vital signs, physical examination results, ECGs, clinical 
laboratory parameters (Appendix B), ISIS 703802 plasma concentrations, immunogenicity and 
biomarker samples, AEs and concomitant medication/procedure information will be performed 
according to the Schedule of Procedures in Appendix A. 
Extensive Pharmacokinetic (PK) Subgroup Only: 
Within each cohort, a subgroup of approximately 12 subjects, who will consent to voluntary 
extensive PK sampling, will undergo additional PK sampling, in what is referred to as the PK 
Subgroup in this study. Subjects in this subgroup will have additional PK sampling time points in 
order to evaluate the plasma PK parameters of ISIS 703802. Subjects in this subgroup will have 
additional visits to the clinic during the treatment period in order to collect blood samples for PK 
assessment (Appendix A and C). 
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 as outlined in Appendix A for 
safety and clinical laboratory evaluations.    
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 10 hours. Any confirmatory test, or test taken for safety reasons, may be taken at any 
time, irrespective of fasting status. During this time subjects can drink water and should ensure 
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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 +/- 2 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 be collected every 14 days 
+/- 2 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 be collected every 
14 days +/- 2 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 8.5.2.   
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 laboratories' 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 is considered an adverse event of special interest and must 
be reported in an expedited fashion to the Sponsor as per Sections 9.3.3 and 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 Sections 9.3.3  
and 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 

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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 platelet 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 
Electrocardiography  
Electrocardiography (ECG) will be conducted at Screening, Day 1, (prior to the first dose of 
Study Drug), and again during the treatment period as follows per dosing cohort: 
• Cohort A at Weeks 5, 13, 21, and 27/ET  
• Cohorts B and C at Weeks 5, 13, 21 and 25/ET 
In all cohorts, 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. 
6.2.3 
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. 
Within each cohort, subjects assigned to the PK Subgroup will have additional PK sampling time 
points and additional visits to the clinic during the treatment period in order to collect blood 
samples for PK assessment (Appendix C). 
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. 

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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 
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 subject. 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 
Study Drug Description 
Study Drug (ISIS 703802 or Placebo) characteristics are listed in Table 1. 
Study Drug (ISIS 703802 or Placebo) will be provided as 0.8 mL deliverable volume in 2 mL 
stoppered and sealed glass vials as a sterile solution.   

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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. 
7.1.1 
ISIS 703802 (ISIS 703802)  
ISIS 703802 vials contain 100 mg/mL ISIS 703802 in water for injection.  Additionally, sodium 
phosphate buffer and sodium chloride are added to control the measure of the acidity or basicity 
of the solution (pH) and tonicity, respectively.  The target pH is 7.4. 
7.1.2 
Placebo  
Placebo vials contain 0.9% sodium chloride in water for injection.  1.6 µg/mL riboflavin is added 
to ensure color matching of placebo vials to ISIS 703802 vials. 
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 703802  
Placebo 
Strength 
100 mg/ mL  
Not Applicable  
Volume/Formulation 
0.8 mL/ per 2.0 mL vial 
0.8 mL/ per 2.0 mL vial 
Route of Administration 
SC* 
SC* 
                       * 
SC = subcutaneous 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ISIS 703802 or placebo) 
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 or placebo) 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. 
8. 
TREATMENT OF SUBJECTS 
8.1 
Study Drug Administration 
Study Drug (ISIS 703802 or placebo) will be administered to subjects by Study Center staff as 
follows: 
Cohort A: a single SC dose of 20 mg every week (weekly) for 26 weeks and 26 doses 
Cohort B: a single SC dose of 40 mg once every 4 weeks for 21 weeks and 6 doses 
Cohort C: a single SC dose of 80 mg once every 4 weeks for 21 weeks and 6 doses 
Self-administration, if applicable, will be allowed after appropriate training of subject and/or 
caregiver. 
Subjects in Cohort A receive 1 dose per week, and subjects in Cohorts B and C should receive 
1 dose every 4 weeks with weeks always defined relative to Study Day 1. For example, if a 

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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 (ISIS 703802 
or placebo) preparation and administration. 
Table 2 
Study Drug Dosing Information 
Cohort 
Treatment 
Volume to Administer/Dose 
# Doses 
Total Study Drug 
A 
20 mg ISIS 703802 
or placebo 
(Every week) 
0.2 mL  
26 
520 mg 
B 
40 mg ISIS 703802 
or placebo 
(Every 4 weeks) 
0.4 mL  
6 
240 mg 
C 
80 mg ISIS 703802 
or placebo 
(Every 4 weeks) 
0.8 mL  
6 
480 mg 
8.2 
Other Protocol-Required Drugs 
No other Study Drug treatments are required by the protocol.  
8.3 
Other Protocol-Required Treatment Procedures 
There are no other treatment procedures required by the protocol 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 the Day 1 value itself. 
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, such as between the central and 
local lab, safety-mandated action must be initiated based on the more critical (lower or higher, as 
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Confirmation Guidance:  At any time during the study (treatment or post-treatment follow-up 
periods), the clinical laboratory results meeting any of 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 (ISIS 703802 or placebo). All new specimen collections should take place as soon as 
possible (ideally within 3 days of the initial collection).  
In addition, as described in Section 6.2 hematology labs should be sent in parallel to the central 
and local laboratory for analysis. 
Stopping Rule Guidance: The Investigator may interrupt or permanently discontinue study 
treatment for any medical reason including 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 or placebo), 
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 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. 

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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 ≤ 2 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 of 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 >1.5x 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. 

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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 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: Estimated GFR (eGFR) (by CKD-EPI 
formula) decrease from Baseline > 25%, urine albumin/creatinine ratio (UACR) > 165 mg/g, 
urine protein/creatinine ratio (UPCR) > 325mg/g, or an increase in serum creatinine from 
Baseline > 0.3 mg/dL, or new onset hematuria defined as ≥5 RBC/hpf (except for menstruating 
females). 
These alert levels are set to anticipate and prevent the risk of a medically significant change in 
renal function while receiving Study Drug. 
Abnormal test results should be repeated. In the event of a confirmed laboratory result meeting 
one or more of the above criteria, the following supplemental renal tests should be obtained 
within 7 days, and additional laboratory studies may be performed to identify if other potential 
etiologies may be a causal factor:  
Serum creatinine, urine culture, 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 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 the study treatment period, 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 

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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  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) platelet count is ≥ 30% decreased from Baseline, or 3) the hematology 
sample is unreportable. All 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 E 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.  
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  

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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 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 a glucometer and asked to record Self Monitored Blood Glucose (SMBG) levels 
weekly 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 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. 

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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 the 
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).  
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 

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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 an 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. 
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 
subject 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 

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pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation/injury  
8.6.2 
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 investigator to require further evaluation, a serum 
creatinine, urine culture, and urine microscopy sample with inspection of sediment should be 
immediately obtained. 
Dosing of a subject with Study Drug (ISIS 703802 or placebo) will be stopped permanently if 
testing in any of the following values is confirmed in the absence of an alternative explanation: 
1. eGFR (CKD-EPI) decrease of > 25% from Baseline 
2. eGFR (CKD-EPI) value < 45 mL/min/1.73 m2 
3. UACR >165mg/g  
4. UPCR >325mg/g 
5. New onset of hematuria  (defined as ≥5 RBC/hpf) 
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.   
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 < 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. 

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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. 
 
 
 

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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 the dose by 50 % as 
follows: 
For Cohort A:  reduce to 10 mg every 
week  
For Cohort B:  reduce to 20 mg every 4 
weeks 
For Cohort C:  reduce to 40 mg every 4 
weeks 
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: 
For Cohort A:  reduce to 10 mg every 
week 
For Cohort B:  reduce to 20 mg every 4 
weeks 
For Cohort C:  reduce to 40 mg every 4 
weeks 
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  
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 24 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). 

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8.6.4 
Stopping Rule for Documented Severe Hypoglycemia 
In the event of a first instance of documented severe hypoglycemia, dosing of a subject with 
Study Drug will be suspended temporarily. The need to adjust the background medication and 
the suitability of the subject for continued dosing will be determined by the Investigator in 
consultation with the Study Medical Monitor. In the event of a second instance of documented 
severe hypoglycemia, after a re-challenge, dosing of a subject with Study Drug will be stopped 
permanently. 
Dose adjustments, including dose interruptions, and/or decreasing the dose or dose frequency 
will be allowed for safety and tolerability. Any proposed adjustments to treatment 
schedule must be discussed with, and approved by, the Study Medical monitor prior to 
initiation.  
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, and the Study Medical Monitor will 
be informed. 
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. 
Subjects who discontinue treatment early should be entered into the post-treatment evaluation 
period.  Every effort should be made to complete the early termination study procedures and 
observations at the time of withdrawal (see Appendix A). 
If a subject discontinues treatment after only 1 dose, then the post-treatment evaluation 
procedures cohorts should be followed.   

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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 (weekly dosing cohort) or 10 (every 
4 week dosing cohorts) 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.  
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 (ET) study procedures and observations at the time of 
withdrawal (see Appendix A).  
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. 

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8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter (OTC) 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 omega-3 
fatty acids should make every effort to remain on the same brand throughout the study. 
8.10.1.1 
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. 
Any medications deemed necessary by the Investigator are allowed in response to an AE that 
requires drug therapy, except those listed in the disallowed concomitant therapy. In such cases, 
the Investigator must consult the Sponsor Medical Monitor to decide on subject continuation or 
withdrawal from the study. 
8.10.1.2 
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 

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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. The Data and Safety Monitoring Board (DSMB) will 
be notified of any SAE as specified in the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness. While the 
Sponsor may upgrade an Investigator’s decision, it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
Appropriate personnel at the Sponsor or designee will unblind SUSARs for the purpose of 
regulatory reporting. The Sponsor or designee will submit SUSARs to Regulatory Agencies in 
blinded or unblinded fashion according to local regulation. The Sponsor or designee will submit 
SUSARs to Investigators in a blinded fashion. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population.  For Study Drug (ISIS 703802 or placebo) “expected” AEs, refer to the Investigator’s 
Brochure. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 

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9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any 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 
9.4 
Monitoring and Recording of 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 

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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:  
 
 
Email:  
 
 
Fax:  
 
 
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. 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 703802 or placebo) is characterized by one 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 or placebo) 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 or placebo) administration and/or exposure suggests that a 
causal relationship is unlikely (For reporting purposes, Unlikely/Remote will be grouped 
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• 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 or placebo) due to the event is characterized by one 
of the following. 
• None: No changes were made to Study Drug (ISIS 703802 or placebo) 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 one of the 
following: 
• AE Persists: Subject terminates from the trial and the AE continues 
• Recovered: Subject recovered completely from the AE 

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• Became Serious: The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable): AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by one 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. 
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 
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• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Study Drug (ISIS 703802 or placebo) 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 (ISIS 703802 or placebo) 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 
Investigators 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 

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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 
Percent change in fasting TG level from Baseline at the primary analysis time point. 
10.1.2 
Secondary Endpoints 
• Absolute and percentage change in ANGPTL3 protein, TC, LDL-C, HDL-C, VLDL-C, 
Non-HDL-C, ApoB (ApoB-48, ApoB-100), ApoCIII, ApoAI, FFA, Lp(a) 
• Absolute change in fasting plasma glucose, HbA1c, fasting insulin HOMA-IR, 
fructosamine and glycated albumin 
• Absolute and percent change in weight, SBP and DBP 
• Absolute and percent change in hepatic fat fraction (HFF) by MRI-PDFF 
• Proportion of subjects reaching hepatic fat fraction (HFF) ≤ 8% by MRI-PDFF 
• Absolute change in Fatty Liver Index (FLI) 
• Absolute change in ALT and AST 
Evaluate the beneficial effect of ISIS 703802 on changes from Baseline at the primary analysis 
time point on: 
• Adipokines and related metabolic markers such as leptin, adiponectin, phospholipids (e.g. 
ceramides, sphingolipids, diacylglycerol) 
• Body composition as measured by single slice MRI of subcutaneous adipose tissue (SAT) 
and visceral adipose tissue (VAT), waist circumference, WHR (waist-to-hip ratio), and 
BMI 
  
 
 
 
 
 
 
 
 
 

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10.2 
Sample Size Considerations 
Subjects in the placebo arm will be pooled for the statistical analysis in order to compare active 
and control arms. Therefore, each of the 4 arms will have 24 patients. Considering 10% 
dropouts, 21 patients per group are expected to complete the study. 
A sample size of 21 patients per arm will be able to detect: 
• A treatment difference in mean triglycerides of 50% based on a between-patient standard 
deviation of 46% (Jani et al. 2014)  and a two-sample t-test with an unadjusted alpha 
level of 0.05 with 93% power. 
• A treatment difference in mean liver fat of 4.75% based on a between-patient standard 
deviation of 3.96% (Tiikkainen et al. 2004) and a two-sample t-test with an unadjusted 
alpha level of 0.05 with 96% power. 
A total of approximately 96 subjects (32 subjects per cohort, including 24 subjects per cohort 
treated with ISIS 703802) will be randomized to ensure that the efficacy of ISIS 703802 will be 
adequately characterized in the study. 
10.3 
Populations 
Full Analysis Set (FAS): All subjects who are randomized, received at least 1 dose of Study 
Drug (ISIS 703802 or placebo), and have a Baseline TG assessment. The FAS represents the 
practically-feasible intent-to-treat (ITT) population as delineated in ICH Guideline E9. This 
population will be used for the primary analysis of efficacy.  
Per Protocol Set (PPS): Subset of the FAS who received within 6 months at least 25 weekly 
doses of Study Drug for subjects randomized to Cohorts A, and at least 5 monthly doses of Study 
Drug for subjects randomized to Cohorts B and C, and who have no major protocol violations 
that could compromise the interpretation of efficacy. Major violations will be determined prior to 
unblinding for statistical analysis. This population will be used for supportive inferences 
concerning efficacy.  
Safety Set: All subjects who are randomized and receive at least 1 dose of Study Drug. This 
population will be used for all safety analyses.  
PK Population: All subjects who are randomized and received at least 1 dose of ISIS 703802, 
and have at least 1 evaluable concentration result post first dose. This population will be used for 
analysis of PK data.  
10.4 
Definition of Baseline 
Baseline for TG, ANGPTL3, TC, LDL-C, HDL-C, VLDL-C, Non-HDL-C, ApoB (ApoB-48, 
ApoB-100), ApoCIII, ApoAI, FFA, Lp(a), and other lipid measurements will be defined as the 
average of Day 1 pre-dose assessment and the last measurement prior to Day 1 pre-dose 
assessment. The Baseline for other measurements is defined as the last non-missing assessment 
prior to the first dose of Study Drug.  
10.5 
Interim Analysis  
No interim efficacy analysis is planned. 

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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. Hypothesis testing will be used for the primary 
efficacy endpoint and select secondary efficacy endpoints.  
All eCRF data, lab data transfers, and any outcomes derived from the data will be provided in the 
subject data listings. Subject data listings will be presented for all subjects 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. Where appropriate, p-values will be reported. All statistical tests will be 
conducted using 2-sided tests with 5% Type I error rate unless otherwise stated.  
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group. The subject disposition will be summarized by treatment group. All subjects 
enrolled will be included in a summary of subject disposition.  
10.6.2 
Safety Analysis 
10.6.2.1 Adverse Events  
Treatment duration and amount of Study Drug (ISIS 703802 or placebo) received will be 
summarized by treatment group. Subject 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 (ISIS 703802 or placebo) will be summarized.  
10.6.2.2 Clinical Laboratory Data  
Laboratory tests to ensure subject safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, complement, etc., will be summarized by study visits for 
each treatment group. These safety variables will also be presented as change and percent change 
from Baseline over time after Study Drug (ISIS 703802 or placebo) administration, as 
appropriate. In addition, the number of subjects who experience abnormalities in clinical 
laboratory evaluations will be summarized by treatment group.  
10.6.2.3 Vital Signs and Examinations  
Vital sign and ECG measures will be tabulated by treatment group.  

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10.6.3 
Efficacy Analysis 
10.6.3.1 Analysis of Primary Efficacy Endpoint  
The primary analysis of the primary endpoint will be the pairwise comparison of percent change 
from Baseline to primary analysis time point in TG between ISIS 703802 treatment groups and 
pooled placebo group in the FAS. The data will be analyzed using an analysis of covariance 
(ANCOVA) model with the Baseline TG as a covariate. Missing data may be handled by LOCF 
or multiple imputation methods (Schafer 1997; Shaffer 1999).  
The primary efficacy analysis will take place after the last subject has completed the primary 
analysis time point, and the database has been locked.  
The following sensitivity analyses will be conducted:  
• The primary analysis will be repeated in the PPS  
• The primary efficacy endpoint will be analyzed using a Wilcoxon Rank Sum test on both 
FAS and PPS, and the treatment effect will be estimated using Hodges-Lehmann 
estimator  
Additional sensitivity analyses may be conducted as appropriate; the details of these analyses 
will be outlined in the SAP. 
10.6.3.2 Analysis of Secondary Efficacy Endpoints  
• Absolute and percentage change at the primary analysis time point in ANGPTL3 protein, 
TC, LDL-C, HDL-C, VLDL-C, Non-HDL-C, ApoB (ApoB-48, ApoB-100), ApoCIII, 
ApoAI, FFA, Lp(a) will be compared between each AKCEA-ANGPTL3-LR treatment 
group and pooled placebo group using an ANCOVA model with Baseline as covariate  
• Absolute change in fasting plasma glucose, HbA1c, fasting insulin HOMA-IR, 
fructosamine and glycated albumin will be compared between each ISIS 703802 
treatment group and pooled placebo group using an ANCOVA model with Baseline as 
covariate  
• Absolute and percent change in weight, SBP and DBP will be compared between each 
ISIS 703802 treatment group and pooled placebo group using an ANCOVA model with 
Baseline as covariate  
• Absolute and percent change in hepatic fat fraction (HFF) by MRI-PDFF will be 
compared between each ISIS 703802 treatment group and pooled placebo group using an 
ANCOVA model with Baseline as covariate  
• Proportion of subjects reaching hepatic fat fraction (HFF) ≤ 8% by MRI-PDFF at the 
primary analysis time point will be compared between each ISIS 703802 treatment group 
and pooled placebo group using a logistic regression model with Baseline HFF as a 
covariate.  

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• Absolute change in Fatty Liver Index (FLI) will be compared between each ISIS 703802 
treatment group and pooled placebo group using an ANCOVA model with Baseline as 
covariate 
• Absolute change in ALT and AST will be compared between each ISIS 703802 treatment 
group and pooled placebo group using an ANCOVA model with Baseline as covariate 
• Absolute change in Adipokines and related metabolic markers such as leptin, 
adiponectin, phospholipids (e.g. ceramides, sphingolipids, diacylglycerol) will be 
compared between each ISIS 703802 treatment group and pooled placebo group using an 
ANCOVA model with Baseline as covariate 
• Absolute change in Body composition as measured by single slice MRI of subcutaneous 
adipose tissue (SAT) and visceral adipose tissue (VAT), waist circumference, WHR 
(waist-to-hip ratio), and BM will be compared between each ISIS 703802 treatment group 
and pooled placebo group using an ANCOVA model with Baseline as covariate 
 
• 
 
 
 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
For all subjects, trough and post-treatment concentrations of ISIS 703802 in plasma (as total 
full-length oligonucleotides, including fully conjugated, partially conjugated, and unconjugated 
ISIS 703802) will be determined and summarized by treatment with and without stratification by 
subject immunogenicity (IM) status using descriptive statistics.  
In addition, plasma terminal elimination half-life of ISIS 703802 will be calculated using the 
post-treatment follow-up data if data permits.  
Additionally, for subjects in the PK subgroup only, PK parameters will be calculated using 
non-compartmental methods. The maximum plasma concentration (Cmax) and time to reach Cmax 
(Tmax) values will be obtained directly from the plasma concentration-time data. The area under 
the plasma concentration-time curve (AUC) values after the first dose and last dose will be 
calculated using the linear trapezoidal rule. Other PK parameters may be calculated at the 
discretion of the PK scientist. Plasma PK parameters will be summarized using descriptive 
statistics with and without stratification by subject IM status.  
Exposure-response relationships between selected PD [e.g., TG] and PK measures (e.g., plasma 
trough concentrations) may be explored (including with and without stratification by IM status) 
in this study, or in a separate population PK analysis combined with other clinical studies.  
The IM of ISIS 703802 will be assessed before, during, and after treatment with Study Drug 
(ISIS 703802 or placebo). The IM incidence (number) and incidence rate (percent) will be 

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summarized at each evaluated study time point and at the subject level by treatment and dose, as 
the total number of and percent of evaluated subjects with antibody negative, positive, and 
unknown status. Study subjects with positive anti-ISIS 703802 antibody status may be further 
classified (when applicable) as being either ‘persistent’, ‘transient’, or not determinable. 
Potential relationships of IM with selected efficacy, safety, and PK measures may be evaluated.  
Additional details regarding the PK and IM analysis will be described in the SAP. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
subject 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 or placebo) 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. 
The sponsor shall maintain all records referred to in the applicable Regulations for a period of 
25 years. 
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 E6R2) 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 
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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. 
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 

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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 (E6R2), 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. 

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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. 
 

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13. 
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DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Number 2, 2014 
Leite NC,  Salles GF, Araujo AL, et al. Prevalence and associated factors of non-alcoholic fatty liver 
disease in patients with type-2 diabetes mellitus. Liver Int. 2009; 29(1):113-9.  

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Martin-Campos JM, Roig R, Mayoral C, et al. Identification of a novel mutation in the ANGPTL3 gene in two 
families diagnosed of familial hypobetalipoproteinemia without APOB mutation. Clin Chim Acta 2012; 413: 552-
555. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274:1715-1722. 
Minicocci I, Montali A, Robciuc MR, et al. Mutations in the ANGPTL3 gene and familial combined hypolipidemia: 
a clinical and biochemical characterization.  J Clin Endocrinol Metab. 2012 Jul; 97(7):E1266-75. 
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, et al. Exome sequencing, ANGPTL3 mutations, and familial combined 
hypolipidemia. N Engl J Med 2010; 363: 2220-2227. 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High 
Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education 
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel III) final report. Circulation. 2002 Dec 17; 106(25):3143-421. 
Noto D, Cefalu AB, Valenti V, et al. Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined 
hypolipidemia. Arterioscler Thromb Vasc Biol 2012; 32: 805-809. 
Pisciotta L, Favari E, Magnolo L, et al. Characterization of three kindreds with familial combined hypolipidemia 
caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet 2012; 5: 42-50. 
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood. 2010; 115(2): 168-86. 
Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using 
triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 2014; 42: 8796-8807. 
Robciuc MR,  Maranghi M, Lahikainen A, et al. ANGPTL3 deficiency is associated with increased insulin 
sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013 
Jul; 33(7):1706-13.  
Romeo S, Yin W, Kozlitina J, et al. Rare loss-of-function mutations in ANGPTL family members contribute to 
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Schafer JL. Analysis of Imcomplete Multivariate Data. Chapman and Hall, A CRC Press Company, US 1997.  
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obesity and diabetes in mice. Am J Physiol Endocrinol Metab 2002; 282: E207-E214. 
Shulman, GI.  Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease N Engl J Med 2014; 
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Vernon G, Baranova A, Younossi ZM. Systematic review: The epidemiology and natural history of NAFLD and 
NAFL in adults. Aliment Pharmacol Ther. 2011; 34(3):274-85. 
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14. 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
Schedule of Procedures – Weekly Dosing 
Schedule of Procedures – Every 4-Week Dosing 
 

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Appendix A Schedule of Procedures – Weekly Dosing 
 
Screeningr 
Treatment Period 
Follow-up 
Period 
Run-in# 
Qual† 
Study Week 
-5 to -1 
-1 to 0 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27/ET 
4* 
8* 
13* 
Study Day 
-35 to -8 
-7 to -1 
1 
2a 
29 
57 
85 
113 
141 
169 
176 
177a 178a 
183 
*Weeks from 
the end of 
treatment 
periodq 
Visit and Testing Window +/- Days 
0 
0 
0 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
3 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
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 
X 
Physical Examination b 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
X  
X 
Waist circumference/ WHR 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 Body Weight and Height c 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X  
 
 
X 
X 
X 
X 
12- lead ECG (triplicate) 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
Ultrasoundp  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI  
Xd, s 
 
 
 
 
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 
Renal Biomarkers g 
X 
 
EVERY 14 DAYS (+/- 2 days) f, g 
X 
X 
X 
 
 
 
X 
Xh 
Xh 
Xh 
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 
Hematology  j, k 
X 
 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS (+/- 2 days) f, k   
Xh 
Xh 
Xh 
Coagulation 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ISIS 703802-CS2 
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Amendment 2 
Protocol 
 
25 October 2018 
 
80 
Appendix A Schedule of Procedures – Weekly Dosing Continued 
 
Screeningr 
Treatment Period 
Follow-up 
Period 
Run-in# 
Qual* 
Study Week 
-5 to -1 
-1 to 0 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27/ET 
4* 
8* 
13* 
Study Day 
-35 to -8 
-7 to -1 
1 
2a 
29 
57 
85 
113 
141 
169 
176 
177a 178a 
183 
* Weeks from 
the end of 
treatment 
periodq 
Visit and Testing Window +/- Days 
0 
0 
0 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
3 
3 
3 
3 
Liver Biomarkers 
 
 
X 
 
 
 
X 
 
X  
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 703802 l 
 
 
X3 
X1 
X 
X 
X 
X 
X 
 
X3 
X1 
X2 
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 
X  
Archived Serum & Plasma 
Samples j, n 
 
 
X 
 
 
X 
 
X 
X  
 
 
 
 
X 
X 
X 
X  
PD Panel and phospholipids 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 
FPG, and delipidated free 
glycerol, insulin j 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Biomarkers of Inflammation 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Study Drug:  SC Injection 
 
 
EVERY WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG  
(Week 1 through Week 26/Day 176) o 
 
 
 
 
Adverse Events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
† Qual =Qualification  
# 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.  
 

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Protocol 
 
25 October 2018 
 
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Appendix A Schedule of Procedures – Weekly Dosing Continued 
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
Visit only required for subjects in PK subgroup. 
b 
Full physical exam will be performed at the Screening visit and an abbreviated physical exam will be performed during treatment and follow-up periods. 
c     Height only required at Screening. 
d     MRI 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.  
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 5 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 
Last dose of Study Drug will be administered at Week 26/Day 176 +/- 3 days. 
p 
Ultrasound to determine positive liver fat at screening will only be performed on patients who do not have documented history of hepatic steatosis as 
determined .by imaging (CT scan, MRI or US). Ultrasound may be repeated at the discretion of the PI. Results of Ultrasound must be available and confirm 
eligibility prior to MRI being performed. 
q 
Treatment period is defined as the time from the first dose through one dosing interval post last dose. 
r 
If a subject was screened and failed to meet eligibility under a previous protocol, the subject may be screened under the current protocol. 
s 
If a subject was screened and had an MRI, but failed to meet eligibility under a previous protocol, the MRI during rescreening may not need to be repeated. 
The need to repeat an MRI for such subjects should be discussed with the Medical Monitor. 
 
Time (time is in reference to Study Drug administration):  
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose for all subjects and pre-dose, 1, 2, 4, 8 hours post SC injection for subjects on PK subgroup. 

ISIS 703802-CS2 
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Amendment 2 
Protocol 
 
25 October 2018 
 
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Appendix A Schedule of Procedures – Every 4-Week Dosing 
 
Screeningr 
Treatment Period 
Follow-up Period 
Run-in# 
Qual† 
Study Week 
-5 to -1 
-1 to 0 
1 
1 
5 
9 
13 
17 
21 
22 
23 
25/ET 
4* 
8* 
13* 
Study Day 
-35 to -8 
-7 to -1 
1 
2a 
29 
57 
85 
113 
141 
142a 143a 148a 155a 
169 
* Weeks from the 
end of treatment 
periodq 
Visit and Testing Window +/- Days 
0 
0 
0 
0 
2 
2 
2 
3 
3 
0 
0 
0  
0  
3 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
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 b 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Waist circumference/ WHR 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Body Weight and Height c 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
12- lead ECG (triplicate) 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
Ultrasoundp  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI  
Xd, s 
 
 
 
 
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 
Renal Biomarkers g 
X 
 
EVERY 14 DAYS (+/- 2 days) f, g 
X 
X 
 
 
 
 
X 
Xh 
Xh  
Xh  
Serum Creatinine and Cys-C i, j, k 
X 
 
EVERY 14 DAYS (+/- 2 days) f, i 
X 
X 
 
 
 
 
X 
X 
X 
X 
Chemistry Panel j  , k 
X 
 
EVERY 14 DAYS f 
X 
X 
 
 
 
 
X 
X 
X 
X 
Hematology  j, k 
X 
 
X 
 HEMATOLOGY PERFORMED EVERY 14 DAYS (+/- 2 days) f, k  
Xh 
Xh 
Xh 
Coagulation 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
25 October 2018 
 
83 
 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
 
Screeningr 
Treatment Period 
Follow-up Period 
Run-in# 
Qual* 
Study Week 
-5 to -1 
-1 to 0 
1 
1 
5 
9 
13 
17 
21 
22 
23 
25/ET 
4* 
8* 
13* 
Study Day 
-35 to -8 
-7 to -1 
1 
2a 
29 
57 
85 
113 
141 
142a 143a 148a 155a 
169 
* Weeks from the 
end of treatment 
periodq 
Visit and Testing Window +/- Days 
0 
0  
0 
0 
2 
2 
2 
3 
3 
0 
0 
0  
0  
3 
3 
3 
3 
Liver Biomarkers 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 703802  l 
 
 
X3 
X1 
X 
X 
X 
X 
X3 
X1 
X2 
X 
X 
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 
X 
X 
X 
PD Panel and phospholipids j 
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 
HbA1C j 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
FPG, and delipidated free glycerol, 
insulin j 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
Biomarkers of Inflammation  
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Study Drug:  SC Injection 
 
 
EVERY 4-WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG  
(Week 1 through Week 21/Day 141) o 
 
 
 
Adverse Events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
†Qual =Qualification  
# 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.  
 
 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
25 October 2018 
 
84 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
Visit only required for subjects in PK subgroup. 
b 
Full physical exam will be performed at the Screening visit and an abbreviated physical exam will be performed during treatment and follow-up periods. 
c     Height only required at Screening. 
d     MRI 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 
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 the follow-up period, hematology sampling for platelet values should continue to be taken every 14 days (+/- 2 days) for 6 weeks after Week 27/EOT, 
then at Week 4, 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 
Last dose of Study Drug will be administered at Week 21/Day 141 +/- 3 days. 
p    Ultrasound to determine positive liver fat at screening will only be performed on patients who do not have a documented history of hepatic steatosis as 
determined.by imaging (CT scan, MRI or US). Ultrasound may be repeated at the discretion of the PI. Results of Ultrasound must be available and confirm 
eligibility prior to MRI being performed. 
q 
Treatment period is defined as the time from the first dose through one dosing interval post last dose. 
r 
If a subject was screened and failed to meet eligibility under a previous protocol, the subject may be screened under the current protocol. 
s 
If a subject was screened and had an MRI, but failed to meet eligibility under a previous protocol, the MRI during rescreening may not need to be repeated. 
The need to repeat an MRI for such subjects should be discussed with the Medical Monitor. 
 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose for all subjects and pre-dose, 1, 2, 4, 8 hours post SC injection for subjects on PK subgroup 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
25 October 2018 
 
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Appendix B 
List of Laboratory Analytes 
 
 

ISIS 703802-CS2 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
25 October 2018 
 
86 
Appendix B List of Laboratory Analytes 
Clinical Chemistry Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Cholesterol 
• 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 
 
Screening Tests 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• HIV antibody 
• FSH (women only) 
• Serum βhCG 
• TSH 
• Free T4 
• Free T3 
 
Coagulation 
• aPTT (sec) 
• PT (sec) 
• INR 
 
Extended Lipid Panel 
• Total Cholesterol 
(TC) 
• LDL cholesterol 
(LDL-C) 
• HDL cholesterol 
(HDL-C) 
• Non-HDL cholesterol 
(non-HDL-C) 
• Triglycerides (TG) 
• VLDL cholesterol 
(VLDL-C) 
• Lp(a) 
• FFA 
• ApoB-48 
• ApoB-100 
• ApoB 
• ApoCIII 
• Apo A-1 
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 (apoptosis 
and fibrosis) 
• 
CK18  
• 
PIIINP  
 
Inflammatory 
• 
hs-CRP 
• 
IL-6 
• 
IFN gamma 
• 
TNF alpha 
• 
Leptin 
• 
Adiponectin 
Extended Urinalysis 
• Routine Urinalysis 
- 
Color 
- 
Appearance 
- 
Specific gravity 
- 
pH 
- 
Protein 
- 
Red Blood Cells 
- 
Glucose 
- 
Ketones 
- 
Bilirubin 
- 
Urobilinogen 
- 
Leukocyte esterase 
- 
Nitrate 
• Microscopic examination 
• P/C Ratio (UPCR) 
• A/C Ratio (UACR) 
 
Renal Urine Biomarkers2 
• NGAL  
• NAG 
• KIM-1 
 
24-Hour Urine Test 
• Creatinine clearance 
• Protein 
• Albumin 
 
Phospholipids 
• 
Ceramides 
• 
Sphingolipids 
• 
Diacyglycerol 
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. 

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Appendix C 
PK Sampling Schedule  
Sampling Schedule for Weekly Dosing Cohort 
Sampling Schedule for Every 4-Week Dosing Cohorts 
 

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Appendix C PK Sampling Schedule for Weekly Dosing Cohort 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
1 
5 
9 
13 
17 
21 
26 
27 
4* 
8* 
13* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
176 
177 
178 
183 
*Weeks from the end of 
treatment period4 
All 
Subjects Pre-dose NA 
Pre-dose Pre-dose Pre-dose Pre-dose Pre-dose Pre-
dose 
NA 
NA 
Anytime 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
Only 
Pre-
dose, 1, 
2, 4, & 8-
hr1 
24-hr2 
Pre-dose Pre-dose Pre-dose Pre-dose Pre-dose 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 
48-hr3 
Anytime 
Anytime 
Anytime 
Anytime 
1 
Window of (-) 2 hrs 
2 
24-hr from previous dose of Study Drug.  Window of (+/-) 4 hours 
3 
48-hr from previous dose of Study Drug.  Window of (+/-) 6 hours 
4 
Treatment period is defined as the time from the first dose through one dosing interval post last dose 
 

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Appendix C PK Sampling Schedule for Every 4-Week Dosing Cohorts 
 
Treatment Period 
Follow-up Period 
Study Week 
1 
1 
5 
9 
13 
17 
21 
22 
23 
25 
4* 
8* 
13* 
Study Day 
1 
2 
29 
57 
85 
113 
141 
142 
143 
148 
155 
169 
*Weeks from the end of 
treatment period4 
All Subjects Pre-dose NA 
Pre-dose Pre-dose Pre-dose Pre-dose Pre-dose NA 
NA 
NA 
NA 
Anytime 
Anytime 
Anytime 
Anytime 
PK Sub-
group only 
Pre-dose, 
1, 2, 4, 
and 8-hr1 
24-hr2 
Pre-dose Pre-dose Pre-dose Pre-dose 
Pre-
dose, 1, 
2, 4, and 
8-hr1 
24-hr2 
48-hr3 Anytime Anytime 
Anytime 
Anytime 
Anytime 
Anytime 
1 
Window of (-) 2 hours allowed 
2 
24-hr from previous dose of Study Drug.  Window of (+/-) 4 hours allowed 
3 
48-hr from previous dose of Study Drug.  Window of (+/-) 6 hours allowed 
4 
Treatment period is defined as the time from the first dose through one dosing interval post last dose 
 
 

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Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 

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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 
2010. 
 
 

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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 
 

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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix E 
Additional Laboratory Tests for Patients with 
Platelet Count <100,000/mm3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix E 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