A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study of ISIS 678354 in Patients With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at Increased Risk for), and/or With Severe Hypertriglyceridemia
Phase: PHASE2
Conditions: Hypertriglyceridemia, Atherosclerotic Cardiovascular Disease, Severe Hypertriglyceridemia
Sponsor: Ionis Pharmaceuticals, Inc.

 
 
A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study of ISIS 678354 in Patients 
With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease (Established or at 
Increased Risk for), and/or With Severe Hypertriglyceridemia 
 
NCT05355402 
 
22 March 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Report 
CONFIDENTIAL 
Ionis Pharmaceuticals, Inc.
Study Number:  ISIS 678354-CS8 
Version 1
16. Appendices 
 
1. 
STUDY INFORMATION 
1.1. 
Protocol and Protocol Amendments 
The protocol was amended 2 times.  The latest version of the protocol (Protocol Amendment 2) 
is provided along with the change summary for the revision. 
Protocol Version 
Date 
Document Provided 
Original 
23 February 2022 
None 
Protocol Amendment 1 
31 August 2022 
None 
Protocol Amendment 2 
22 March 2023 
Protocol and change summary 
 
Page 1 of 86

 
 
IONIS PHARMACEUTICALS, INC. 
 
ISIS 678354-CS8 
 
A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study 
of ISIS 678354 in Patients with Hypertriglyceridemia and 
Atherosclerotic Cardiovascular Disease (Established or at Increased 
Risk for), and/or with Severe Hypertriglyceridemia  
 
Amendment 2 – 22 March 2023 
 
 
Trial Sponsor 
Ionis Pharmaceuticals, Inc.  
2855 Gazelle Court 
Carlsbad, CA 92010 
Telephone Number:  +1 760-603-4665 
Fax Number:  +1 760-603-2625 
Key Sponsor Contact and Signatory 
 PhD 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
Mobile: 
 
Email: 
Sponsor Medical Monitor 
, MD, PhD 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
Mobile: 
E-mail: 
 
 
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ISIS 678354-CS8 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
22 March 2023 
 
2 
ISIS 678354-CS8 
 
Amendment 2 
 
Clinical Phase:  [2b] 
 
A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study 
of ISIS 678354 in Patients with Hypertriglyceridemia and 
Atherosclerotic Cardiovascular Disease (Established or at Increased 
Risk for), and/or with Severe Hypertriglyceridemia  
 
 
Protocol History 
Original Protocol:  
23 February 2022 
Amendment 1: 
31 August 2022 
 
 
 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA  92010 
 
See electronic signature and date attached at end of document 
 
 MD 
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. that must not be disclosed to anyone 
other than the recipient study staff and members of the independent ethics committee, institutional review board, or 
authorized regulatory agencies.  This information cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Ionis Pharmaceuticals, Inc. 
Page 3 of 86
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ISIS 678354-CS8 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
22 March 2023 
 
3 
Protocol Signature Page 
 
Protocol Number: 
ISIS 678354-CS8 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study of ISIS 
678354 in Patients with Hypertriglyceridemia and Atherosclerotic 
Cardiovascular Disease (Established or at Increased Risk for), and/or with 
Severe Hypertriglyceridemia  
Amendment:  
Amendment 2 
Date:  
 
22 March 2023 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, identified 
above, 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 and the Declaration of Helsinki. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
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ISIS 678354-CS8 
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PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 678354-CS8 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study of 
ISIS 678354 in Patients with Hypertriglyceridemia and Atherosclerotic 
Cardiovascular Disease (Established or at Increased Risk for), and/or 
with Severe Hypertriglyceridemia 
Amendment Number: 
2 
Amendment Date: 
22 March 2023 
The following modifications to Protocol ISIS 678354-CS8 Amendment 1, dated 31 August 2022, 
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. 
Protocol Section 
Description of Change 
Rationale 
Section 8.5.2 Safety 
Monitoring and Permanent 
Stopping Rules for Renal 
Function 
Rules for interrupting, 
restarting and permanently 
stopping treatment with 
Study Drug were 
modified. 
Due to the large variability of renal 
function tests (eGFR, UPCR, and UACR) 
within individuals, renal safety 
monitoring rules across the olezarsen 
program are being updated to focus on 
clinically significant changes in renal 
function. These changes are being made 
across all olezarsen trials and have been 
endorsed by the DSMB. 
Section 8.5.3 Safety 
Monitoring Rules for 
Platelet Count Results 
Citrate sample for PLTs 
was removed from the list 
of additional lab analyses 
(Platelet Panel, Table 3). 
Platelet count results using citrate tubes 
are not as reliable as EDTA tubes and can 
provide artificially lower values.  Use of 
sodium citrate samples resulted in 
decrease of platelet count by 36.8% to 
48.5% when compared to use of EDTA in 
an analysis performed by Medpace 
Reference Laboratories.  
Section 8.5.6 Safety 
Monitoring for Potential 
Hypersensitivity Reactions 
Language was edited to 
more clearly note 
symptoms of a 
hypersensitivity reaction 
and that they should be 
managed per standard of 
care 
To provide clearer language regarding 
safety monitoring 
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Protocol Section 
Description of Change 
Rationale 
Section 8.7.1 Follow-up 
Visits for Early Termination 
from Treatment Period or 
Post Treatment Follow-up 
Period 
Language was edited 
noting that patients should 
be encouraged to attend all 
remaining landmark visits 
Edited for clarity to note that the intent is 
that patients attend all landmarks visits 
regardless of when they discontinued 
treatment 
Section 9.3.4 Adverse Event 
of Special Interest 
Information was updated 
noting which events are 
considered Adverse 
Events of Special Interest 
(AESI). 
Provided for clarity and to add 
pre-treatment to avoid a hypersensitivity 
reaction as an AESI. 
Section 10.3 Populations 
The definition of Full 
Analysis Set (FAS) was 
updated by removing “and 
who have at least 1 
post-baseline TG 
assessment”. 
To include all subjects who are 
randomized and received any dose of 
Study Drug in the FAS, regardless of 
availability of post-baseline TG 
assessment. 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT .........................................................................................................4 
EXECUTIVE SUMMARY ...........................................................................................................12 
Study Design ..................................................................................................................................13 
Inclusion/Exclusion Criteria ..........................................................................................................14 
Key Inclusion Criteria: ...................................................................................................................14 
STUDY DESIGN AND TREATMENT SCHEMA ......................................................................16 
STUDY GLOSSARY ....................................................................................................................17 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................19 
1.1. 
Objectives ...................................................................................................................19 
1.1.1. 
Primary Objective .......................................................................................................19 
1.1.2. 
Secondary Objective(s) ...............................................................................................19 
1.1.3. 
Exploratory Objectives ...............................................................................................19 
1.1.4. 
Safety and Tolerability Objective ...............................................................................19 
1.1.5. 
Pharmacokinetic (PK) Objective ................................................................................19 
1.2. 
Study Endpoints ..........................................................................................................19 
1.2.1. 
Primary Endpoint ........................................................................................................19 
1.2.2. 
Secondary Endpoint(s) ................................................................................................19 
1.2.3. 
Exploratory Endpoint(s) .............................................................................................20 
1.2.4. 
Safety and Tolerability Endpoints ..............................................................................20 
1.2.5. 
Pharmacokinetic (PK) Endpoint(s) .............................................................................20 
2. 
BACKGROUND AND RATIONALE .......................................................................20 
2.1. 
Overview of Disease ...................................................................................................20 
2.2. 
Therapeutic Rationale .................................................................................................21 
2.3. 
Olezarsen (ISIS 678354) .............................................................................................23 
2.3.1 
Mechanism of Action .................................................................................................23 
2.3.2 
Chemistry ....................................................................................................................23 
2.3.3 
Preclinical Experience ................................................................................................23 
2.3.4 
Clinical Experience .....................................................................................................23 
2.4 
Rationale for Dose and Schedule of Administration ..................................................24 
2.5 
Benefit-Risk Assessment ............................................................................................25 
2.5.1 
Overall Assessment of Benefit:  Risk .........................................................................25 
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2.5.2 
Additional Risks During the COVID-19 Pandemic ...................................................25 
3 
EXPERIMENTAL PLAN ..........................................................................................26 
3.1 
Study Design ...............................................................................................................26 
3.2 
Number of Study Centers ...........................................................................................26 
3.3 
Number of Patients .....................................................................................................26 
3.4 
Overall Study Duration and Follow-up ......................................................................26 
3.4.1 
Screening Period .........................................................................................................27 
3.4.2 
Treatment Period ........................................................................................................27 
3.4.3 
Post-Treatment Follow-up Period ...............................................................................27 
3.5 
End-of-Study ...............................................................................................................27 
3.6 
Data and Safety Monitoring Board or Independent Data Monitoring 
Committee ...................................................................................................................27 
3.7 
Allowances in the Circumstance of a Public Health Emergency ...............................27 
4 
PATIENT ENROLLMENT ........................................................................................29 
4.1 
Screening ....................................................................................................................29 
4.2 
Randomization ............................................................................................................29 
4.3 
Replacement of Patients .............................................................................................29 
4.4 
Unblinding of Treatment Assignment ........................................................................29 
5 
PATIENT ELIGIBILITY ...........................................................................................30 
5.1 
Inclusion Criteria ........................................................................................................30 
5.2 
Exclusion Criteria .......................................................................................................32 
6 
STUDY PROCEDURES ............................................................................................33 
6.1 
Study Schedule ...........................................................................................................33 
6.1.1 
Screening ....................................................................................................................33 
6.1.2 
Treatment Period ........................................................................................................34 
6.1.3 
Post Treatment Follow-up Period ...............................................................................34 
6.2 
Additional Study Assessments ...................................................................................34 
6.2.1 
Laboratory Assessments .............................................................................................34 
6.2.2 
Physical Exams and Vital Signs .................................................................................36 
6.2.3 
Electrocardiography ....................................................................................................36 
6.2.4 
Pharmacokinetic Sampling .........................................................................................36 
6.2.5 
Pancreatitis Medical History .......................................................................................36 
6.3 
Requirements on the Lifestyle of Patients ..................................................................36 
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6.3.1 
Prevention of Pregnancy .............................................................................................36 
6.3.2 
Other Requirements ....................................................................................................37 
7 
STUDY DRUG ...........................................................................................................37 
7.1 
Study Drug Description ..............................................................................................37 
7.2 
Packaging and Labeling ..............................................................................................38 
7.3 
Study Drug Accountability .........................................................................................38 
8 
TREATMENT OF PATIENTS ..................................................................................38 
8.1 
Study Drug Administration.........................................................................................38 
8.2 
Other Protocol-Required Drugs ..................................................................................38 
8.3 
Other Protocol-Required Treatment Procedures ........................................................38 
8.4 
Treatment Precautions ................................................................................................38 
8.5 
Safety Monitoring and Permanent Stopping Rules ....................................................39 
8.5.1 
Safety Monitoring and Permanent Stopping Rules for Liver Chemistry Tests ..........39 
8.5.2 
Safety Monitoring and Permanent Stopping Rules for Renal Function .....................41 
8.5.3 
Safety Monitoring and Permanent Stopping for Platelet Count Results ....................42 
8.5.4 
Safety Monitoring and Permanent Stopping Rules for Bleeding Events ...................44 
8.5.5 
Safety Monitoring for Constitutional Symptoms .......................................................45 
8.5.6 
Safety Monitoring for Potential Hypersensitivity Reactions ......................................45 
8.5.7 
Safety Monitoring for Triglyceride and Apolipoprotein B Elevations .......................46 
8.6 
Adjustment of Dose and/or Treatment Schedule ........................................................46 
8.7 
Discontinuation of Study Drug Administration ..........................................................46 
8.7.1 
Follow-up Visits for Early Termination from Treatment Period or 
Post-Treatment Follow-up Period ...............................................................................47 
8.8 
Withdrawal of Patients from the Study Procedures ....................................................48 
8.8.1 
Lost to Follow-up .......................................................................................................48 
8.9 
Concomitant Therapy and Procedures ........................................................................49 
8.9.1 
Concomitant Therapy .................................................................................................49 
8.9.2 
Concomitant Procedures .............................................................................................49 
8.10 
Treatment Compliance ................................................................................................49 
9 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................50 
9.1 
Sponsor Review of Safety Information ......................................................................50 
9.2 
Regulatory Reporting Requirements ..........................................................................50 
9.3 
Definitions ..................................................................................................................50 
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9.3.1 
Adverse Event .............................................................................................................50 
9.3.2 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction ............51 
9.3.3 
Serious Adverse Event (SAE) ....................................................................................51 
9.3.4 
Adverse Event of Special Interest ...............................................................................52 
9.4 
Monitoring and Recording Adverse Events ...............................................................52 
9.4.1 
Serious Adverse Events ..............................................................................................52 
9.4.2 
Non-Serious Adverse Events ......................................................................................53 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) .........................................53 
9.4.3.1 
Relationship to the Study Drug...................................................................................53 
9.4.3.2 
Severity .......................................................................................................................54 
9.4.3.3 
Action Taken with Study Drug ...................................................................................54 
9.4.3.4 
Treatment Given for Adverse Event ...........................................................................54 
9.4.3.5 
Outcome of the Adverse Event ...................................................................................54 
9.4.3.6 
Follow-up of Adverse Event .......................................................................................55 
9.5 
Procedures for Handling Special Situations ...............................................................56 
9.5.1 
Abnormalities of Laboratory Tests .............................................................................56 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................56 
9.5.3 
Dosing Errors ..............................................................................................................57 
9.5.4 
Contraception and Pregnancy .....................................................................................57 
10 
STATISTICAL CONSIDERATIONS .......................................................................58 
10.1 
Stratification, Subsets, and Covariates .......................................................................58 
10.2 
Sample Size Considerations .......................................................................................58 
10.3 
Populations .................................................................................................................58 
10.4 
Definition of Baseline, Month 6 and Month 12 ..........................................................59 
10.5 
Interim Analysis and Multiplicity ...............................................................................59 
10.5.1 
Unblinded Interim Safety Analysis ............................................................................59 
10.5.2 
Multiplicity for the Final Efficacy Analysis ...............................................................59 
10.6 
Planned Methods of Analysis .....................................................................................60 
10.6.1 
Demographic and Baseline Characteristics ................................................................60 
10.6.2 
Safety Analysis ...........................................................................................................60 
10.6.3 
Efficacy Analysis ........................................................................................................61 
10.6.3.1 
Analysis of Primary Endpoint ....................................................................................61 
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10.6.3.2 
Analysis of Secondary Endpoints ...............................................................................63 
10.6.4 
Pharmacokinetic Analysis ..........................................................................................64 
10.6.5 
Additional/Exploratory Analyses ...............................................................................65 
11 
INVESTIGATOR’S REGULATORY OBLIGATIONS ...........................................65 
11.1 
Informed Consent .......................................................................................................65 
11.2 
Ethical Conduct of the Study ......................................................................................66 
11.3 
Independent Ethics Committee/Institutional Review Board ......................................66 
11.4 
Patient Confidentiality ................................................................................................66 
12 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................67 
12.1 
Protocol Amendments ................................................................................................67 
12.2 
Study Termination ......................................................................................................67 
12.3 
Study Documentation and Storage .............................................................................67 
12.4 
Study Monitoring ........................................................................................................68 
12.5 
Language .....................................................................................................................69 
12.6 
Compensation for Injury .............................................................................................69 
13 
REFERENCES ...........................................................................................................70 
14 
APPENDICES ............................................................................................................73 
APPENDIX A. SCHEDULE OF PROCEDURES .....................................................................74 
APPENDIX B. LIST OF LABORATORY ANALYTES ..........................................................76 
APPENDIX C. PK AND ADA SAMPLING SCHEDULE ........................................................77 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES ..............................................................78 
APPENDIX E. GUIDELINES FOR MANAGEMENT OF 
HYPERTRIGLYCERIDEMIA (LIFE-STYLE INTERVENTIONS 
AND STANDARD OF CARE LIPID LOWERING THERAPY) .....................81 
APPENDIX F. CLINICAL DIAGNOSIS OF ASCVD AND METABOLIC 
SYNDROME ........................................................................................................84 
 
 
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LIST OF TABLES 
Table 1: 
Study Drug Characteristics .........................................................................................38 
Table 2: 
Actions in Patients with Low Platelet Count ..............................................................43 
Table 3: 
Platelet Panel ..............................................................................................................44 
 
LIST OF FIGURES 
Figure 1: 
A Schematic Overview of the Possible Effects of ApoC-III on TRL 
Metabolism .................................................................................................................22 
 
 
 
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EXECUTIVE SUMMARY 
Title:  A Randomized, Double-blind, Placebo-Controlled, Phase 2b Study of Olezarsen 
(ISIS 678354) in Patients with Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease 
(Established, or at Increased Risk for), or with Severe Hypertriglyceridemia.  
Phase:  2b. 
Investigational Product:  Olezarsen. 
Population:  Adult males and females with hypertriglyceridemia [fasting TG ≥ 150 mg/dL 
(1.69 mmol/L)] and clinical diagnosis or increased risk of atherosclerotic cardiovascular disease 
(ASCVD) and adult males and females with severe hypertriglyceridemia [fasting TG 
≥ 500 mg/dL (5.65 mmol/L)] with or without ASCVD. 
Objectives 
Corresponding Endpoints 
Primary: 
To evaluate the effect of Olezarsen on 
percent change in fasting triglyceride 
(TG) levels compared to placebo 
 
The primary endpoint is the percent change in fasting TG 
from Baseline at Month 6 (average of weeks 25 and 27) 
compared to placebo 
Secondary: 
To evaluate the effect of Olezarsen as 
compared to placebo on: 
• 
Percent change in fasting TG levels 
upon longer duration of treatment 
(1 year) 
• 
Proportion of patients who achieve 
different thresholds in fasting TG   
 
 
 
• 
Percent change in fasting TG from Baseline at 
Month 12 (average of Week 51 and Week 53) 
compared to placebo 
• 
Proportion of patients who achieve fasting 
TG < 150 mg/dL (1.69 mmol/L) at Month 6 and 
proportion of patients who achieve fasting 
TG < 150 mg/dL at Month 12 compared to placebo in 
the subgroup of patients with baseline TG < 500 mg/dL 
• 
Proportion of patients who achieve fasting 
TG < 500 mg/dL (5.65 mmol/L) at Month 6 and 
proportion of patients who achieve fasting 
TG < 500 mg/dL at Month 12 compared to placebo in 
the subgroup of patients with baseline TG ≥ 500 mg/dL 
• 
Percent change in fasting 
apolipoprotein C-III (apoC-III), very 
low-density lipoprotein cholesterol 
(VLDL-C), remnant cholesterol, 
non-high-density lipoprotein 
cholesterol (non-HDL-C), high 
density lipoprotein cholesterol 
(HDL-C), total cholesterol (TC), 
apoB, low- density lipoprotein 
cholesterol (LDL-C), and apoA-1 
• 
Percent change in fasting apoC-III, VLDL-C, remnant 
cholesterol, non-HDL-C, HDL-C, TC, apoB, LDL-C, 
and apoA-1 from Baseline at Month 6 and at Month 12 
compared to placebo 
 
 
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Objectives 
Corresponding Endpoints 
Secondary (Continued): 
• 
Adjudicated acute pancreatitis event 
rate in patients with ≥ 2 events of 
adjudicated acute pancreatitis in 
5 years prior to enrollment 
• 
Adjudicated acute pancreatitis event 
rate 
 
• 
Adjudicated acute pancreatitis event rate during the 
Treatment Period compared to placebo in patients with 
≥ 2 events of adjudicated acute pancreatitis in 5 years 
prior to enrollment 
• 
Adjudicated acute pancreatitis event rate during the 
Treatment Period compared to placebo 
Exploratory: 
Major adverse cardiovascular events 
(MACE) 
 
• 
Events rates of independently adjudicated major 
adverse cardiovascular events (MACE). 
• 
Additional analyses of MACE composite of CV death, 
non-fatal MI, non-fatal ischemic stroke, and arterial 
revascularization (coronary and non-coronary), and the 
triple composite of CV death, non-fatal MI, and 
non-fatal ischemic stroke may be performed depending 
on rates of MACE. 
Safety and Tolerability: 
To evaluate safety and tolerability of 
olezarsen 
 
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 
receiving Olezarsen will be compared with those receiving 
placebo 
Pharmacokinetics (PK): 
To evaluate PK of olezarsen 
 
Plasma trough and post-treatment concentrations of 
Olezarsen 
 
Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled study done in conjunction 
with the TIMI Study Group, an academic research organization based at Brigham and Women’s 
Hospital and Harvard Medical School.  Eligible patients will enter an approximately 4-week 
Screening Period (that may be extended to 8 weeks if assessments cannot be completed within 
the 4-week period) that includes an at least 2-week Diet/ Life-style Stabilization/Run-In Period, 
and an approximately 2-week Qualification Period.  Following Qualification, approximately 
152 eligible patients will be randomized 1:1 to Cohort A (50 mg) or Cohort B (80 mg) and each 
cohort further randomized 3:1 to receive olezarsen or placebo in a 53-week Treatment Period.  
Patients in Cohort A will receive 50 mg of olezarsen once every 4 weeks or matching volume of 
placebo (0.5 mL) during Weeks 1-49 of the Treatment Period.  Patients in Cohort B will receive 
80 mg olezarsen once every 4 weeks or matching volume of placebo (0.8 mL) during 
Weeks 1-49 of the Treatment Period.  The 80 mg dose (blinded olezarsen or placebo) may be 
adjusted to 50 mg every 4 weeks due to tolerability or safety reasons at any point during the 
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study following consultation with the Sponsor Medical Monitor or designee.  Randomization 
will be stratified by Qualification fasting TG levels of <500 mg/dL vs ≥ 500 mg/dL.  Following 
the Week 53 visit, patients will enter the 13-week Post-Treatment Follow-Up Period.  
All endpoints will be evaluated after the last patient has completed the Week 53/ET Visit.   
See Appendix A for a list of activities and their timing. 
Inclusion/Exclusion Criteria 
Key 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. Aged ≥ 18 years at the time of informed consent 
3. Fall into at least 1 of the following groups (a or b): 
a. Hypertriglyceridemia with fasting TG ≥ 150 mg/dL (1.69 mmol/L) and < 500 mg/dL 
(5.65 mmol/L) with either 
• Clinical diagnosis of ASCVD defined as documented coronary artery disease 
(CAD), cerebrovascular disease, or peripheral artery disease (Appendix F), or 
• At increased risk for ASCVD defined as: 
− Type 2 Diabetes mellitus, or 
− Two (2) or more of the following cardiovascular (CV) risk enhancing factors:   
− Men ≥55 years of age or women ≥ 65 years of age 
− Women with a history of preeclampsia, or premature menopause (before 
the age of 40 years) 
− Family history of premature ASCVD (before the age of 55 years for 
males, or before the age of 65 years for females) 
− Current tobacco use (5 cigarettes/day or more for at least 1 year) 
− Metabolic syndrome (see Appendix F for definition) 
− Hypertension requiring antihypertensive treatment 
− Chronic kidney disease stage 3 or (eGFR 30-59 mL/min/M2) 
− LDL-C ≥ 160 mg/dL 
− LDL-C ≥ 100 mg/dL on therapy to lower LDL-C 
− Elevated high-sensitivity C-reactive protein (≥ 2.0 mg/L) 
− Elevated lipoprotein (a) (≥ 50 mg/dL or 125 nmol/L) 
− Ankle brachial index < 0.9 in asymptomatic patients 
− Coronary artery calcium score ≥ 100 
b. Severe hypertriglyceridemia with fasting TG ≥ 500 mg/dL (5.65 mmol/L)  
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Note:  TG levels must meet inclusion criteria at both the Screening Run-In Visit and the 
Screening Qualification Visit.  If the fasting TG is below the required level at a Visit, up to 
2 additional tests may be performed with the average of the tests used to consider eligibility at 
that Visit. 
4. Patients should be on standard of care (SOC) lipid-lowering medications per local 
guidelines (Appendix E).  Lipid-lowering medications should be optimized and stabilized 
for at least 4 weeks prior to Screening to minimize changes in these medications during 
the study.  Patients taking over-the-counter (OTC) omega-3 fatty acids should make 
every effort to remain on the same brand through the end of the study. 
A full list of inclusion criteria is provided in Section 5.1. 
Key Exclusion Criteria 
1. Diabetes with any of the following: 
a. Newly diagnosed within 12 weeks of Screening 
b. HbA1c ≥ 9.5% at Screening 
c. Change in basal insulin regimen > 20% within 3 months prior to Screening  
d. For patients with type 1 diabetes:  episode of diabetic ketoacidosis, or ≥ 3 episodes of 
severe hypoglycemia within 6 months prior to Screening 
2. Acute coronary syndrome or stroke/TIA within 6 months prior to Screening  
3. Major surgery, peripheral revascularization, or non-urgent percutaneous coronary 
intervention (PCI) within 3 months prior to Screening, or upcoming planned major 
surgery or major procedure (e.g., arterial revascularization) during the course of the study 
4. Active pancreatitis within 4 weeks prior to Screening 
A full list of exclusion criteria is provided in Section 5.2. 
Statistical Analyses:  
With 33 patients in each olezarsen treatment group and 22 in the pooled placebo group, there 
would be an approximately 80% power to detect a 60% difference between each olezarsen 
treatment group and pooled placebo group at an alpha level of 0.05 (two-sided), assuming 
60% reduction in the olezarsen treatment group, no change in the placebo patients, and a 
common standard deviation (SD) of approximately 73%.  It is estimated that drop-out rate is 
approximately 20%.  Approximately 152 patients will be enrolled in this trial to account for 
potential early dropouts and to facilitate general safety evaluations.  
Additional details regarding statistical analyses are provided in Section 10.   
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STUDY GLOSSARY 
Abbreviation Definition 
ADA 
anti-drug antibody 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
ASCVD 
atherosclerotic cardiovascular disease 
ASGPR 
asialoglycoprotein receptor 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase  
BP 
blood pressure 
BUN 
blood urea nitrogen 
CAD 
coronary artery disease 
CIR 
copy increment from reference 
CRNMB 
clinically relevant non-major bleeding 
CTCAE 
Common Terminology Criteria for Adverse Events  
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
ER 
emergency room 
eCRF 
electronic Case Report Form 
eGFR 
estimated GFR 
FAS 
Full Analysis Set 
FCS 
Familial Chylomicronemia Syndrome 
FSH 
follicle-stimulating hormone 
GalNAc3 
triantenary N-acetyl galactosamine 
GCP 
Good Clinical Practice 
HAV 
hepatitis A virus 
Hb 
Hemoglobin 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL-C 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IDL 
intermediate density lipoprotein 
IEC/IRB 
Independent Ethics Committee/ Institutional Review Board 
IgM 
immunoglobulin M 
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IM 
Immunogenicity 
INR 
international normalized ratio 
ISIS 678354 
antisense inhibitor of apoC-III, olezarsen 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
LPL 
lipoprotein lipase 
MACE 
major adverse cardiovascular event 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
MPV 
mean platelet volume 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
Non-HDL-C 
Non-high density lipoprotein chloesterol 
NSAID 
non-steroidal anti-inflammatory drug 
on study 
The patient is ‘on study’ from signing of the informed consent until their last study visit 
OTC 
over-the-counter 
PCI 
percutaneous coronary intervention 
PD 
pharmacodynamic(s) 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PLT 
platelet 
PPS 
per protocol set 
PT 
prothrombin time 
RDW 
red cell distribution width 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA strand in RNA/DNA 
hybrids 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SHTG 
severe hypertriglyceridemia 
SOC 
standard of care 
Study Day 1 
defined as the first day Study Drug is administered to the patient 
Study Drug 
olezarsen or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
TC 
total cholesterol 
TG 
Triglyceride(s)  
TRL 
triglyceride-rich lipoproteins 
UACR 
urine albumin/creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein/creatinine ratio 
VLDL 
very low-density lipoprotein 
VLDL-C 
very low-density lipoprotein cholesterol 
VLDL-TG 
very low-density lipoprotein triglyceride 
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1. 
OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives 
1.1.1. 
Primary Objective 
To evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels 
compared to placebo. 
1.1.2. 
Secondary Objective(s) 
To evaluate the effect of olezarsen as compared to placebo on: 
• Percent change in fasting TG levels upon longer duration of treatment (1 year) 
• Proportion of patients who achieve different thresholds in fasting TG   
• Percent change in fasting apolipoprotein C-III (apoC-III), very low-density lipoprotein 
cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol 
(non-HDL-C), high- density lipoprotein cholesterol (HDL-C), total cholesterol (TC), 
apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and 
apolipoprotein A-1 (apoA-1) 
• Adjudicated acute pancreatitis event rate in patients with ≥ 2 events of adjudicated acute 
pancreatitis in 5 years prior to enrollment 
• Adjudicated acute pancreatitis event rate 
1.1.3. 
Exploratory Objectives 
To evaluate the effect of olezarsen on MACE 
1.1.4. 
Safety and Tolerability Objective  
To evaluate safety and tolerability of olezarsen. 
1.1.5. 
Pharmacokinetic (PK) Objective 
To evaluate PK of olezarsen. 
1.2. 
Study Endpoints 
1.2.1. 
Primary Endpoint 
Percent change in fasting TG from Baseline at Month 6 (average of weeks 25 and 27) compared 
to placebo. 
1.2.2. 
Secondary Endpoint(s) 
• Percent change in fasting TG from Baseline at Month 12 (average of Week 51 and 
Week 53) compared to placebo. 
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• Proportion of patients who achieve fasting TG < 150 mg/dL (1. 69 mmol/L) at Month 6 
and proportion of patients who achieve fasting TG < 150 mg/dL at Month 12 compared 
to placebo in the subgroup of patients with baseline TG < 500 mg/dL (5.65 mmol/L). 
• Proportion of patients who achieve fasting TG < 500 mg/dL (5.65 mmol/L) at Month 6 
and proportion of patients who achieve fasting TG < 500 mg/dL at Month 12 compared 
to placebo in the subgroup of patients with baseline TG ≥ 500 mg/dL. 
• Percent change in fasting apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, HDL-C, 
TC, apoB, LDL-C, and apoA-1 from Baseline at Month 6 and at Month 12 compared to 
placebo. 
• Adjudicated acute pancreatitis event rate during the Treatment Period compared to 
placebo in patients with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment. 
• Adjudicated acute pancreatitis event rate during the Treatment Period compared to 
placebo. 
1.2.3. 
Exploratory Endpoint(s) 
• Events rates of independently adjudicated major adverse cardiovascular events (MACE). 
• Additional analyses of MACE composite of CV death, non-fatal MI, non-fatal ischemic 
stroke, and arterial revascularization (coronary and non-coronary), and the triple 
composite of CV death, non-fatal MI, and non-fatal ischemic stroke may be performed 
depending on rates of MACE. 
1.2.4. 
Safety and Tolerability Endpoints  
Safety and tolerability assessments include:  adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, electrocardiogram (ECG), and use of concomitant 
medications.  Safety and tolerability results in patients receiving olezarsen will be compared with 
those receiving placebo. 
1.2.5. 
Pharmacokinetic (PK) Endpoint(s) 
Plasma trough and post-treatment concentrations of olezarsen, and potential exposure/response 
relationship for apoC-III and TG. 
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
Elevated levels of TGs in the range of 150-500 mg/dL (1.69- 5.65 mmol/L), and triglyceride-rich 
lipoproteins (TRLs) are consistently associated with higher risk for atherosclerotic 
cardiovascular disease (ASCVD) in epidemiological, genetic and clinical studies, even in 
subjects with well controlled LDL-C levels (Nordestgaard and Varbo 2014; Schwartz et al. 2015; 
Nichols et al. 2018; Langsted et al. 2020).   
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Severe hypertriglyceridemia (SHTG) is characterized by extremely high serum TG 
(≥ 500 mg/dL, 5.65 mmol/L), with the predominant elevations of dietary-derived chylomicrons, 
but also with varying degrees of elevated TRLs carrying remnant cholesterol (Brahm and Hegele 
2015).  The etiology of SHTG is multifactorial and due to both genetic, metabolic and 
environmental influences (NCEP 2002; Brown et al. 2012; Dron et al. 2020).   
Patients with sustained chylomicronemia have numerous medical and cognitive complications 
(Chait and Brunzell 1992; Gaudet et al. 2016; Brown et al. 2018), but the frequent occurrence of 
acute and recurrent acute pancreatitis is the major cause of morbidity and even mortality.  Acute 
pancreatitis results from the inflammatory changes caused by excessive chylomicronemia, and 
can be fatal or lead to pancreatic damage (Symersky et al. 2006). 
Standard therapeutic TG-lowering agents are relatively ineffective in lowering 
hypertriglyceridemia associated with chylomicronemia overall, and especially below a threshold 
above which pancreatitis occurs.  This is because fibrates, fish oils and niacin predominantly 
lower TG levels by inhibiting very low-density lipoprotein (VLDL) output from the liver but 
these agents have almost no effect on chylomicron synthesis and release into the circulation, 
which occurs in the intestine, and/or minimal effects on clearance of chylomicrons from plasma. 
In summary, in the absence of effective therapy, patients with modest elevations of TGs as well 
as those with SHTG are at increased risk of CV events, and acute pancreatitis, respectively, and 
represent populations with a major unmet medical need. 
2.2. 
Therapeutic Rationale 
Apolipoprotein C-III (apoC-III) is a component of TRLs and a key regulator of plasma TG levels 
by modulating TRL hepatic uptake through lipoprotein lipase (LPL)-dependent and 
LPL-independent mechanisms (Gaudet et al. 2015; Norata et al. 2015) (Figure 1).  
ApoC-III is a potent inhibitor of LPL (Lemieux et al. 2003) and at higher concentrations also 
inhibits hepatic lipase activity (Kinnunen and Ehnolm 1976), an enzyme which plays an 
important role in the conversion of dense VLDL to intermediate density lipoprotein (IDL) and to 
low-density lipoprotein (LDL) (Brown et al. 2010; Mendivil et al. 2010), as well as in the 
remodeling of HDL (Brown et al. 2010).  In addition, increased apoC-III content adversely 
affects apoE-mediated hepatic uptake of TG-rich remnants (Breyer et al. 1999).  Thus, elevated 
plasma apoC-III levels are associated with impaired hydrolysis and retarded clearance of TG-rich 
particles, resulting in the accumulation of very low-density lipoprotein triglyceride (VLDL-TG) 
and chylomicrons in plasma and the development of hypertriglyceridemia (Ito et al. 1990). 
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Figure 1: 
A Schematic Overview of the Possible Effects of ApoC-III on TRL 
Metabolism  
From (Gordts et al. 2016); apoC-III = apolipoprotein CIII, CR = chylomicron remnant, HL = hepatic lipase, 
IDL = intermediate-density lipoprotein, LDL = low-density lipoprotein, LDL-R = LDL receptor, 
LPL = lipoprotein lipase, LRP1 = low-density lipoprotein receptor related protein 1, SDC1 = syndecan-1, 
VLDL = very low-density lipoprotein. 
 
Human genetic data have demonstrated positive phenotype associations with loss (e.g., null or 
nonsense mutations) and negative effects with gain of function mutations (Atzmon et al. 2006; 
Pollin et al. 2008; Petersen et al. 2010).  A novel nonsense mutation in the APOC3 gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and lower LDL-C, increased HDL-C and 
reduced atherosclerosis (Pollin et al. 2008).  In another study involving a group of 
214 Ashkenazi Jews of advanced age (had passed or nearly reached 100 years of age), genotype 
analysis revealed a polymorphism in the apoC-III gene (APOC3-641CC genotype) with a clear 
pattern of age-dependent frequency that was associated with significantly lower levels of 
apoC-III protein, a favorable lipoprotein profile and increased longevity (Atzmon et al. 2006).  
In contrast to the Amish and Ashkenazi apoC-III polymorphisms associated with lower plasma 
TG, apoC-III polymorphisms associated with higher plasma TG have also been described 
(Petersen et al. 2010).  In a cohort of lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) 
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Asian Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear postprandial 
TG from the circulation.   
It has been suggested that apoC-III may exert proatherogenic effects directly by enhancing vessel 
wall inflammation and indirectly by promoting hypertriglyceridemia (Taskinen et al. 2019).  
Lowering of apoC-III levels with olezarsen in clinical studies involving healthy volunteers and 
patients with high TGs and ASCVD demonstrated TG reduction (as described in Section 2.3.4).   
2.3. 
Olezarsen (ISIS 678354) 
Olezarsen is an antisense oligonucleotide (ASO) inhibitor of apoC-III production.  Specifically, 
olezarsen is a second-generation 2ʹ-O-methoxyethyl chimeric ASO covalently bound to 
triantenary N-acetyl galactosamine (GalNAc3), a high affinity ligand for the hepatocyte-specific 
asialoglycoprotein receptor (ASGPR) (Prakash et al. 2014).  The ASO portion of olezarsen, 
volanesorsen, is designed to bind to the human apoC-III messenger ribonucleic acid (mRNA) 
and has demonstrated robust pharmacology in healthy volunteers and patients, including patients 
with the most severe form of hypertriglyceridemia, FCS (Graham et al. 2013; Gaudet et al. 2014; 
Gaudet et al. 2015).  Olezarsen, having a GalNAc3 conjugate, targets the ASGPR to dramatically 
increase uptake of the ASO to hepatocytes, thereby decreasing the doses needed to reduce 
apoC-III over the unconjugated parent molecule, ISIS 304801.  Olezarsen, therefore, has the 
potential to lower apoC-III and TG with an enhanced tolerability profile over the parent 
molecule, ISIS 304801. 
2.3.1 Mechanism of Action 
The hybridization (binding) of olezarsen to the cognate mRNA results in the RNase H1-mediated 
degradation of the apoC-III mRNA, thus preventing production of the apoC-III protein.  
Maximal antisense-mediated reduction of target mRNA levels is typically greater than 90% of 
control levels in sensitive tissues (Bennett 2007; 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, olezarsen is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages, with a 5′-trishexylamino-(THA)-
C6GalNAc3 endcap. 
2.3.3 Preclinical Experience 
Detailed information concerning the preclinical studies conducted with olezarsen can be found in 
the Investigator’s Brochure.   
2.3.4 Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 678354 (olezarsen) can 
be found in the Investigator’s Brochure.  In addition, the results of the ISIS 678354-CS1 Phase 1 
study, and Phase 2 study are provided in the respective  publications (Alexander et al. 2019; 
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Tardif et al. 2022).  A short summary of the Phase 2 study conducted with ISIS 678354 is 
included below. 
The Phase 2 study was a multicenter, randomized, double-blind, placebo-controlled, 
dose-ranging study.  A total of 114 patients with established ASCVD, or being at risk for 
ASCVD, with fasting TG levels of ≥ 200 mg/dL and ≤ 500 mg/dL, and on standard-of-care 
preventative therapy for their known ASCVD risk factors were treated with subcutaneous (SC) 
injections of ISIS 678354 or matching placebo in the range of dosing equivalent to monthly drug 
exposure of 10 mg to 50 mg, for 6 to 12 months.  Significant reductions in fasting TG levels 
from Baseline to the primary analysis time point at Month 6 were observed in all 
ISIS 678354-treated groups compared to placebo.  The highest dose group (50 mg every 
4 weeks) achieved mean 62% reduction from Baseline in fasting TG levels compared to placebo, 
associated with mean 74% reduction from Baseline in apoC-III, 57% of reduction in VLDL, and 
20% reduction in non-HDL-C levels.  The proportion of patients achieving normal fasting TG 
levels < 150 mg/dL showed a significant, dose-dependent increase in all ISIS 678354 treated 
groups with over 90% (20/22) patients treated with the highest dose of 50 mg Q4W vs. only 
4.2% (1/24) patients treated with placebo achieving this threshold. 
ISIS 678354 was well-tolerated, there was low incidence of predominantly mild injection site 
reactions (12.2% vs. 4.2%), and flu-like reactions (8.9% vs. 8.3%) in patients treated with 
ISIS 678354 compared to placebo, respectively.  No dose- or time-dependent changes in 
platelet (PLT) count were observed, and no patient had a confirmed PLT count < 100,000/mm3.  
No patient met any liver monitoring rules including increase in ALT or AST > 3 × ULN, or 
> 2 × baseline (if baseline > × ULN).  The incidence of patients meeting any renal monitoring 
rules (decrease from Baseline in Estimated GFR [eGFR] > 25%, increase in serum creatinine 
> 0.3 mg/dL, urine albumin/creatinine ratio (UACR) > 250 mg/g, urine protein/creatinine ratio 
(UPCR) > 500 mg/g) was comparable between the pooled placebo group (20.8%) and the pooled 
ISIS 678354 group (17.8%). 
2.4 
Rationale for Dose and Schedule of Administration 
The 50 mg and 80 mg doses of olezarsen once every 4 weeks were chosen based on the 
pre-clinical data, the pharmacodynamic (PD) and safety analysis of the Phase 1 study in healthy 
volunteers with hypertriglyceridemia, and the results of Phase 2 study in patients with ASCVD 
and elevated fasting TG levels.  
The highest dose that was tested in the Phase 2 study was 50 mg every 4 weeks and was found to 
be safe and well tolerated, however TG levels were reduced by no more than 60%.  Higher doses 
are expected to be more effective based on the results from the Phase 1 study demonstrating 
dose-dependent PD effect on the target, apoC-III, with a clear difference in the TG-lowering 
effect between the range of ISIS 678354 doses of 10 mg to 120 mg (per month equivalent) as 
compared to placebo. 
Therefore, the present study will also evaluate the 80 mg dose of olezarsen that is expected to 
reduce fasting TG levels by more than 60% in patients with ASCVD, and to likely reduce TG 
levels below 880 mg/dL in substantial number of patients with SHTG, maximizing the 
opportunity to provide an impact on the risk of pancreatitis.  Therefore, more experience with 
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this dose is needed.  Currently 80 mg dose of olezarsen is being tested in patients with familial 
chylomicronemia syndrome (FCS), as well as in patients with SHTG. 
2.5 
Benefit-Risk Assessment 
2.5.1 Overall Assessment of Benefit:  Risk  
The benefits of treatment of olezarsen are currently unknown.  Due to its mechanism of action 
and based on the previous clinical experience, olezarsen has the potential to be efficacious for the 
treatment of patients with ASCVD or SHTG. 
No specific risks have been identified with olezarsen in the Phase 1 (678354-CS1) or 
Phase 2 (678354-CS2) studies.  The conjugated nature of olezarsen allows specific targeting of 
ASO to hepatocytes so, that for similar hepatocyte exposure, reduced exposure to both 
non-parenchymal liver cells and systemic exposure has the potential to lower apoC-III and TGs 
with an enhanced safety and tolerability profile over the parent molecule, ISIS 304801.   
Nevertheless, regular monitoring of PLT counts, liver chemistry, and renal function, and 
stopping rules will be included in the clinical study as described in Section 8.5.   
Taking into account the measures implemented to minimize risk to patients participating in this 
study, the potential risks identified in association with olezarsen are justified by the anticipated 
benefits that may be afforded to patients in this study. 
Detailed information concerning the benefit-risk assessment of ISIS 678354 can be found in the 
Investigator’s Brochure.   
2.5.2 Additional Risks During the COVID-19 Pandemic 
Patients treated for hyperlipidemia should continue their regular regimen of diet and lifestyle 
measures and should also continue any approved pharmaceutical interventions for lipid lowering 
as no risks have been identified that would cause termination of treatment during the COVID-19 
Pandemic (Iqbal et al. 2020) at this time. 
There could be risk however, for patients who are participating in a clinical trial such as 
olezarsen.  There may be risks to patients traveling to research sites.  Sites should follow their 
specific regional guidance (i.e., institutional, local, state, federal, country-level, as applicable) 
with regard to in person evaluation patients for clinical trials.  In person visits should continue as 
planned as long as it is deemed safe to do so.  Provision will be available for patients to be 
treated or evaluated in their homes by a home healthcare professional.  Additional mitigation 
steps and a study pause may be necessary as conditions warrant.  If a study patient becomes 
infected with COVID-19 or develop COVID-19-related symptoms, the patient should notify the 
study staff/Investigator and notify their treating Physician that they are participating in a clinical 
trial with olezarsen. 
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3 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled study done in conjunction 
with the TIMI Study Group, an academic research organization based at Brigham and Women’s 
Hospital and Harvard Medical School.  Eligible patients will enter an approximately 4-week 
Screening Period (that may be extended to 8 weeks if assessments can’t be completed within the 
4-week period) that includes an at least 2-week Diet/life-style Stabilization/Run-in Period, and 
an approximately 2-week Qualification Period.  Following Qualification, approximately 
152 eligible patients will be randomized 1:1 to Cohort A (50 mg) or Cohort B (80 mg) and each 
cohort further randomized 3:1 to receive olezarsen or placebo in a 53-week Treatment Period.  
Patients in Cohort A will receive 50 mg of olezarsen once every 4 weeks or matching volume of 
placebo (0.5 mL) during Weeks 1-49 of the Treatment Period.  Patients in Cohort B will receive 
80 mg olezarsen once every 4 weeks or matching volume of placebo (0.8 mL) during 
Weeks 1-49 of the Treatment Period.  The 80 mg dose (blinded olezarsen or placebo) may be 
adjusted to 50 mg every 4 weeks due to tolerability or safety reasons at any point during the 
study following consultation with the Sponsor Medical Monitor or designee.  Randomization 
will be stratified by Qualification fasting TG levels of < 500 mg/dL vs. ≥ 500 mg/dL.  Following 
the Week 53 visit, patients will enter the 13-week Post-Treatment Follow-up Period.  All 
endpoints will be evaluated after the last patient has completed the Week 53/ET Visit.   
The patients, Investigators, study staff, and the Sponsor are to remain blinded to lipid data 
(central and local) starting after the first dose on Day 1 then throughout the remainder of 
the study or as noted for TG or apoB alerts per Section 8.5.7 of the protocol. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Approximately 152 patients are planned to be enrolled in this study.   
3.4 
Overall Study Duration and Follow-up 
The study for an individual patient will generally consist of the following periods: 
• Up to 8-week Screening Period 
• A 53-week Treatment Period during which olezarsen or placebo will be administered 
as an every 4-week SC injection (Week 1 through Week 49) 
• A 13-week Post-Treatment Follow-up Period 
Collection and measurement of vital signs, clinical laboratory parameters (including hematology, 
serum chemistry, and urinalysis), adverse events (AE), concomitant medication/procedure 
information, lipid panel, olezarsen plasma concentrations, anti-drug antibody (ADA) testing, 
PLT panel, and ECGs will be performed according to the schedule of procedures in Appendix A.   
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3.4.1 Screening Period 
A period of up to 8 weeks is given to complete the screening and baseline assessments outlined 
in the Schedule of Procedures in Appendix A.   
3.4.2 Treatment Period 
The Treatment Period is 53 weeks.  Eligible patients will have assessments at specified intervals 
throughout the 53-week Treatment Period as outlined in the Schedule of Procedures in 
Appendix A.  During the Treatment Period, Study Drug is administered by SC injection once 
every 4 weeks. 
3.4.3 Post-Treatment Follow-up Period 
The Post-Treatment Follow-up Period is 13 weeks with assessments as outlined in the Schedule 
of Procedures in Appendix A.   
3.5 
End-of-Study 
The End-of-Study is defined as last patient, last visit. 
For individual patients, End-of-Study is defined as completion of their last study visit. 
3.6 
Data and Safety Monitoring Board or Independent Data Monitoring 
Committee  
An independent Data and Safety Monitoring Board (DSMB) consisting of experts in medical 
specialties relevant to the safety of ASO drugs will be assembled to review safety, tolerability 
and efficacy (as needed) data collected on ISIS 678354 during this study.  Based on its ongoing 
assessment of the safety and tolerability of olezarsen, the DSMB will provide recommendations 
to the trial’s Sponsor and academic leadership for modifying, stopping or continuing the study as 
planned.  Details on the medical specialties of the members, safety assessments, frequency of 
review, meeting schedules and controlled access to unblinded data are outlined in the DSMB 
Charter and/or Statistical Analysis Plan (SAP).   
3.7 
Allowances in the Circumstance of a Public Health Emergency 
If an investigative site or the clinical trial patients associated with that site experience a public 
health emergency, such as a pandemic, then throughout that time the following changes to what 
is written elsewhere in this protocol are permissible, at the discretion of the Investigator, 
provided that all International Conference on Harmonization (ICH), Good Clinical Practice 
(GCP), and regulatory requirements associated with the study are still upheld.  These allowances 
may be implemented at any stage of the study:  Screening Period, Treatment Period, and 
Post-Treatment Follow-up Period.  What is considered a public health emergency is based on 
circumstances and procedures at the site, and the judgment of the Investigator.  The time at 
which a public health emergency has resolved to sufficient extent such that these allowances are 
no longer applicable is based on the judgment of the Investigator in consultation with the 
Medical Monitor. 
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• Remote assessments and at-home visits (as allowed by local regulatory 
authorities):  Even when an investigative site remains open to clinical trial patients 
coming on site, social distancing strategies may result in some patients being 
unwilling or unable to attend protocol-specific clinic visits.  For such reasons, 
scheduled clinic visits may be replaced by remote assessments (via video conference 
or telephone call) or at-home visits or a combination, provided that these are properly 
documented.  This may be accomplished by at-home visits by Study Center staff or 
home healthcare providers, with incorporation of videoconference or telephone 
assessments by Study Center staff or designee 
• Randomization:  When a patient is found to be eligible for the study, the decision 
regarding if and when the patient will be randomized is based on the judgment of the 
Investigator in consultation with the Medical Monitor.  Randomization may be 
delayed by up to 1 month without rescreening 
• Safety assessments:  Every effort should be made to continue performing safety 
assessments on schedule.  This may require remote assessments (e.g., for adverse 
events and concomitant medications) by Study Center staff, and it may require at 
home visits (e.g., for blood draws, urine samples, physical examination, vital signs) 
by Study Center staff or home healthcare providers.  Which safety assessments are 
considered critical, for example to support a decision on whether to administer the 
next scheduled dose of Study Drug to a patient, is to be determined on a case-by case 
basis by the Investigator in consultation with the Medical Monitor  
• Reporting of protocol deviations:  All protocol deviations that are caused by a 
public health emergency should be documented as such; for example, include in the 
description of the protocol deviation that it is related to COVID-19.  The impact such 
protocol deviations had on the study is to be summarized in the clinical study report.  
This summary is considered sufficient notification of the EC/IRB for minor protocol 
deviations that were caused by a public health emergency 
• Laboratory assessments associated with primary or secondary endpoints:  Every 
effort should be made to perform the assessments on schedule 
• To support Study Drug administration at home, delivery of Study Drug to the 
patient may be undertaken at the discretion of the Investigator, and if agreed by the 
patient, based on local and regional regulations for transporting investigational 
product 
• Immunization of patients with a vaccine for COVID-19, or antiviral treatments under 
an emergency use authorization for COVID-19, outside of a clinical trial, may occur 
while patients are on study, however it is preferable that a separation of at least 7 days 
occurs between administration of the vaccine or antiviral and administration of Study 
Drug.  Adjustment of the schedule for monthly administration of Study Drug may be 
considered in order to achieve this separation.  In addition, Study Drug should not be 
injected into the same anatomical location as the vaccine for COVID-19. 
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4 
PATIENT ENROLLMENT 
4.1 
Screening 
Before patients 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), as 
appropriate, approval of the protocol, informed consent form, and all other patient directed 
information and/or recruitment material. 
Patients or their legally acceptable representatives must sign and date the consent form before 
any screening tests or assessments are performed.  At the time of consent, the patient will be 
considered enrolled into the study and will be assigned a unique screening number before any 
study procedures, including screening procedures, are performed.  The screening number and 
patient identification number must remain constant throughout the entire trial.  Patients may be 
re-screened in order to determine eligibility.  However, re-screening will not be allowed if the 
patient screen-failed due to not meeting TG criteria.  In the event the patient is re-consented and 
re-screened the patient must be given a new screening number.  Screening numbers and patient 
identification numbers, once assigned, will not be re-used. 
Eligible patients will enter an approximately 4-week Screening Period (that may be extended to 
8 weeks if assessments can’t be completed within the 4-week period) that includes an at least 
2-week Diet/ life-style Stabilization/Run-in Period and a 2-week Qualification Period. 
4.2 
Randomization  
Following Qualification, eligible patients will be randomized 1:1 to Cohort A (50 mg) or 
Cohort B (80 mg) and each cohort further randomized 3:1 to receive olezarsen or placebo in a 
53-week Treatment Period.  Patients in Cohort A will receive 50 mg of olezarsen once every 
4 weeks or matching volume of placebo (0.5 mL) during Weeks 1–49 of the Treatment Period.  
Patients in Cohort B will receive 80 mg olezarsen once every 4 weeks or matching volume of 
placebo (0.8 mL) during Weeks 1-49 of the Treatment Period.  Randomization will be stratified 
by Qualification fasting TG levels of < 500 mg/dL vs. ≥ 500 mg/dL. 
4.3 
Replacement of Patients 
Patients who withdraw from the study may not be replaced. 
4.4 
Unblinding of Treatment Assignment 
The Sponsor and all patients, monitors, and Study Center personnel related to the study, (except 
for the DSMB and statistical/programming support staff) will be blinded throughout the study 
until all patients have completed the study and the database has been locked.  Representatives 
from the Sponsor may be unblinded after the last patient has completed the end of the Treatment 
Period (Week 53/ET) as described in the Unblinding Plan.  Those Sponsor representatives will 
no longer be involved in the conduct of the study after they have been unblinded.  
However, if a patient has suffered a serious adverse event (SAE) (as defined in Section 9.3.3), 
and if the rare circumstance occurs where knowledge of the treatment assignment will impact the 
clinical management of the patient, the Investigator will have the ability to unblind the treatment 
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assignment for that patient using the Interactive Response Technology (IRT).  Participant safety 
must always be the first consideration in making such determination.  If the Investigator decides 
that unblinding is warranted, the Investigator should make every effort to contact the Sponsor or 
TIMI Hotline prior to unblinding a participant’s treatment assignment unless this could delay 
further management of the participant.  The investigator is not required to discuss un-blinding if 
he/she feels that emergent unblinding is necessary.  If a participant’s treatment assignment is 
unblinded, the Sponsor must be notified within 24 hours after breaking the blind. 
The Sponsor or designee will be informed of the unblinding of a patient within 24 hours.  An 
unblinded randomization schema will be maintained securely at the Sponsor’s designated 
vendor.  In addition, all suspected unexpected serious adverse reaction (SUSARs) will be 
unblinded by the Sponsor or designee for the purpose of unblinded regulatory reporting (see 
Section 9.2). 
5 PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 8 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. Aged ≥ 18 years at the time of informed consent 
3. Fall into at least 1 of the following groups (a or b): 
a. Hypertriglyceridemia with fasting TG ≥ 150 mg/dL (1.69 mmol/L) and < 500 mg/dL 
(5.65 mmol/L) with either 
• Clinical diagnosis of ASCVD defined as documented coronary artery disease 
(CAD), cerebrovascular disease, or peripheral artery disease (Appendix F), or 
• At increased risk for ASCVD defined as: 
− Type 2 Diabetes mellitus, or  
− Two (2) or more of the following cardiovascular (CV) risk enhancing factors:  
− 
Men ≥ 55 years of age or women ≥ 65 years of age 
− 
Women with a history of preeclampsia, or premature menopause (before 
the age of 40 years) 
− 
Family history of premature ASCVD (before the age of 55 years for 
males, or before the age of 65 years for females) 
− 
Current tobacco use (5 cigarettes/day or more for at least 1 year) 
− 
Metabolic syndrome (see Appendix F for definition) 
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− 
Hypertension requiring antihypertensive treatment 
− 
Chronic kidney disease stage 3 or (eGFR 30-59 mL/min/M2) 
− 
LDL-C ≥ 160 mg/dL 
− 
LDL-C ≥ 100 mg/dL on therapy to lower LDL-C 
− 
Elevated high-sensitivity C-reactive protein (≥ 2.0 mg/L) 
− 
Elevated lipoprotein (a) (≥ 50 mg/dL or 125 nmol/L) 
− 
Ankle brachial index < 0.9 in asymptomatic patients 
− 
Coronary artery calcium score ≥ 100 
b. Severe hypertriglyceridemia with fasting TG ≥ 500 mg/dL (5.65 mmol/L)  
Note:  TG levels must meet inclusion criteria at both the Screening Run-In Visit and the 
Screening Qualification Visit.  If the fasting TG is below the required level at a Visit, up to 
2 additional tests may be performed with the average of the tests used to consider eligibility at 
that Visit. 
4. Patients should be on standard of care (SOC) lipid-lowering medications per local 
guidelines (Appendix E).  Lipid-lowering medications should be optimized and stabilized 
for at least 4 weeks prior to Screening to minimize changes in these medications during 
the study.  Patients taking over-the-counter (OTC) omega-3 fatty acids should make 
every effort to remain on the same brand through the end of the study 
5.  Patients must be willing to comply with diet and lifestyle recommendations as able 
6 Satisfy the following: 
a. Females:  must be non-pregnant and non-lactating and either: 
• 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) 
• 
post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and follicle-stimulating hormone (FSH) 
levels in the postmenopausal range for the laboratory involved) 
• 
abstinent* or 
• 
if engaged in sexual relations of childbearing potential, agree to use a highly 
effective contraceptive method from the time of signing the informed consent 
form until at least 30 weeks after the last dose of Study Drug (olezarsen or 
placebo) 
b. Males:  Surgically sterile, abstinent*, or if engaged in sexual relations with a female 
of childbearing potential, patient is utilizing a highly effective contraceptive method 
from the time of signing the informed consent form until at least 30 weeks after the 
last dose of Study Drug (olezarsen or placebo) 
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* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are 
not acceptable methods of contraception. 
5.2 
Exclusion Criteria 
1. Diabetes with any of the following: 
a. Newly diagnosed within 12 weeks of screening 
b. HbA1c ≥ 9.5% at Screening 
c. Change in basal insulin regimen > 20% within 3 months prior to Screening 
d. For patients with type 1 diabetes:  episode of diabetic ketoacidosis, or ≥ 3 episodes of 
severe hypoglycemia within 6 months prior to Screening 
2. Acute coronary syndrome or stroke/TIA within 6 months prior to Screening  
3. Major surgery, peripheral revascularization, or non-urgent percutaneous coronary 
intervention (PCI) within 3 months prior to Screening, or upcoming planned major 
surgery or major procedure (e.g., arterial revascularization) during the course of the study  
4. Active pancreatitis within 4 weeks prior to Screening 
5. Screening laboratory results as follows, or any other clinically significant abnormalities 
in screening laboratory values that would render a patient unsuitable for inclusion: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3.0 × ULN 
b. Total bilirubin >1.5 ULN unless due to Gilbert’s syndrome 
c. Estimated GFR (eGFR) < 30 mL/min/1.73 m2 [as determined by the CKD-EPI 
formula for creatinine clearance; (Levey et al. 2009)] 
d. Urine protein/creatinine ratio (UPCR) ≥ 500 mg/g  
6. Uncontrolled arterial hypertension (BP > 180/100 mmHg) despite antihypertensive 
therapy 
7. Uncontrolled hypothyroidism such as those with thyroid stimulating hormone (TSH) 
>1.5× ULN and free thyroxine (T4) < LLN, clinical evidence of hypothyroidism, or 
thyroid hormone therapy that has not been stable for ≥ 4 weeks prior to Screening 
8. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 or active Covid-19 infection with or without therapy that 
will not be resolved by Study Day 1 
9. Active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B 
(e.g., HBsAg positive) diagnosed by initial serological testing and confirmed with RNA 
testing, or prior treatment for hepatitis C.  Patients at Screening who test positive by 
serology (for example, positive for Hepatitis C antibody), but negative by RNA may be 
allowed in consultation with the Sponsor Medical Monitor or designee 
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10. Malignancy within 5 years of Screening, except for non-melanoma skin cancers, cervical 
in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that has 
been successfully treated.  Patients with a history of other malignancies that have been 
treated with curative intent and which have no recurrence within 5 years may also be 
eligible if approved by the Sponsor Medical Monitor or designee 
11. Hypersensitivity to the active substance or to any of the excipients (olezarsen or placebo) 
12. Treatment with another investigational drug (non-oligonucleotide), biological agent, or 
device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is 
longer 
13. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid 
[siRNA]) within 4 months of Screening or 5 half-lives, whichever is longer.  This 
exclusion does not apply to vaccines 
14. Concomitant medication/procedure restrictions: 
a. Systemic corticosteroids or anabolic steroids within 6 weeks prior to Screening and 
during the study unless approved by the Sponsor Medical Monitor or designee 
b. Use of bile acid resins such as colestipol, cholestyramine, or colesevelam within 
4 weeks prior to Screening or planned during the study 
c. Plasma apheresis within 4 weeks prior to Screening or planned during the study 
d. Change in medications known to exacerbate hypertriglyceridemia such as certain beta 
blockers, thiazides, isotretinoin, oral antidiabetic medications, tamoxifen, estrogens or 
progestins within 4 weeks prior to Screening 
e. Change in atypical antipsychotic medications (e.g., olanzapine and clozapine) within 
3 months prior to Screening 
15. Blood or plasma donation of 50 to 499 mL within 30 days of Screening or of > 499 mL 
within 60 days of Screening 
16. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
17. Have any other conditions, including current or recent (< 1 year) alcohol abuse or other 
substance abuse, which, in the opinion of the Investigator would make the patient 
unsuitable for inclusion, or could interfere with the patient participating in or complete 
the study 
6 STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined Appendix A, Appendix B, and Appendix C.   
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 8-week period is provided for 
completing screening assessments and determining patient eligibility for the study.  Abnormal 
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screening results may be re-tested for determination of patient eligibility after consultation with 
the Sponsor Medical Monitor or designee.  Patients may be re-screened in order to determine 
eligibility.  However, re-screening will not be allowed if the patient screen-failed due to not 
meeting TG criteria.   
During the Screening Period, patients will undergo a medical history and physical examination 
including vital signs, 12-lead ECG and have blood and urine samples taken for clinical 
laboratory testing.  Patients will be screened for HIV, hepatitis B and hepatitis C. 
As part of the Screening Period, patients will have at least 2 weeks of Diet/life-style 
Stabilization/Run-in Period, followed by an approximately 2 -week Qualification Period, during 
which final eligibility assessments will be performed.  At the Qualification Visit, TGs will be 
measured. 
Race & Ethnicity data will be collected as part of the demographic information for all screened 
patients during the Screening Period. 
6.1.2 
Treatment Period 
The Treatment Period is defined as the time between the first and the last dose of Study Drug 
plus 1 dosing interval (4 weeks) post-last dose.  Patients will receive Study Drug administered by 
SC injection once every 4 weeks during Weeks 1-49 of the 53-week Treatment Period.   
Collection and measurement of vital signs, physical examination results, ECGs, laboratory 
parameters (Appendix B), olezarsen plasma concentrations, ADA and biomarker samples, AEs 
and concomitant medication/procedure information will be performed according to the Schedule 
of Procedures in Appendix A. 
6.1.3 
Post Treatment Follow-up Period 
After completion of the Week 53 visit assessments, patients will enter the 13-week 
Post-Treatment Follow-up Period.   
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study as per the Schedule of 
Procedures in Appendix A.  A list of these analytes is contained in Appendix B. 
Routine blood chemistry and lipid samples should be taken after fasting for at least 10 hours.  
Water and medications are not restricted during the fast, and the patient should ensure that they 
consume sufficient water in order to not become dehydrated. 
Any confirmatory test, or test taken for safety reasons, may be taken at any time, irrespective of 
fasting status, but ideally no later than 7 days after the initial result is obtained. 
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 
7 days). 
Hematology samples will be collected monthly during the Treatment Period, and at every visit 
during the Follow-up Period.  In the event that a hematology sample is unreportable (e.g., due to 
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hemolyzed or clumped blood samples), the patient’s next scheduled dose should ideally not be 
administered until another sample is repeated and determined not to have met a PLT count 
stopping rule.  The Investigator or designee will contact the patient to hold dosing until a new 
PLT count is obtained and reviewed.  Use of home care provider or local laboratory (as 
described below) should be considered. 
Investigators may, at their discretion, test specific laboratory parameters (except for those which 
must remain blinded e.g., lipid panel) which may be prone to clotting, clumping or hemolysis 
(e.g., hematology samples) at a local laboratory, in addition to the required central laboratory 
samples.  In these instances, the local laboratory results should be recorded by the site into the 
electronic database.  Assays which are blinded should not be locally tested and recorded into the 
database (e.g., lipid panel). 
Blood and urine samples for renal function testing will also be collected monthly during the 
Treatment Period, and at every visit during the Follow-up Period, and sent to the central 
laboratory for analysis as per Section 8.5.2. 
Liver chemistry testing will also be collected monthly during the Treatment Period, and at every 
visit during the Follow-up Period, and sent to the central laboratory for analysis as per 
Section 8.5.1. 
All lab samples are to be sent to the central laboratory by overnight courier and processed.  Lab 
alerts issued 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.  All lab sample results 
from local laboratories are received by the Study Center staff per the local laboratories’ standard 
reporting time and should be entered as soon as possible (ideally within 1 week) into the 
electronic Case Report Form (eCRF) to inform the Sponsor and CRO study monitoring teams. 
All PLT count results must be reviewed promptly (within 2 business days of receipt) by the 
Investigator, or designee, to ensure that the count has not met a dose interruption or stopping 
rule.  Any case of PLT count reduction to levels below 50,000/mm3 accompanied by a major 
bleeding (MB) event or clinically relevant non-major bleeding event (CRNMB) , or PLT count 
of < 25,000/mm3 independent of a MB or CRNMB event, is considered an AE of special interest 
(AESI) and must be reported in an expedited fashion to the Sponsor as per Section 9.3.4 and 
Section 9.4.1.   
All liver and renal function tests must also be reviewed promptly (within 2 business days of 
receipt) by the Investigator, or designee, to ensure that the result has not met the stopping rule.  
All lab alerts received, including those related to PLT, 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 according to the Medical Data Surveillance Plan.   
Further information on safety monitoring and actions to be taken by the Study Investigator are 
provided in Section 8.5. 
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6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure (BP), and pulse rate, and may 
also include respiratory rate and body temperature.  Height will be measured at Screening. 
6.2.3 
Electrocardiography 
Electrocardiography will be conducted at Screening, Day 1 (prior to the first dose of Study 
Drug), and again at the end of the Treatment Period (Week 53) and the end of the Post-Treatment 
Follow-up Period as outlined in Appendix A.   
6.2.4 
Pharmacokinetic Sampling 
Blood samples for the determination of plasma olezarsen concentrations will be collected prior to 
dosing on Day 1 and at various times throughout the treatment and Post-Treatment Follow-up 
Period as noted in the table in Appendix A and Appendix C. 
6.2.5 
Pancreatitis Medical History 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 5 years prior 
to Screening and information relating to these events will be collected for independent 
adjudication. 
6.3 
Requirements on the Lifestyle of Patients  
6.3.1 
Prevention of Pregnancy 
Every effort must be made to prevent pregnancy throughout the entire study.  All male patients 
and women of childbearing potential must refrain from sperm/egg donation and either be 
abstinent† or practice highly effective contraception from the time of signing the informed 
consent form until at least 30 weeks after their last dose of Study Drug.  
For the purposes of this study, females of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age 
or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post-hysterectomy 
For the purposes of the study, highly effective contraception is defined as follows: 
For male patients: 
• Highly effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, surgically sterile via bilateral orchidectomy, or the 
non-pregnant female partner of childbearing potential uses a highly effective 
contraceptive method (defined below) 
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For female patients and female partners of male patients, highly effective contraception methods 
comprise: 
• Surgical sterilization (e.g., bilateral tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy), hormonal contraception associated with 
inhibition of ovulation (combined estrogen and progestogen containing, or 
progestogen-only), intrauterine contraception device or intrauterine 
hormone-releasing system (IUS), or the male partner uses highly effective 
contraceptive method (defined above).  For female subjects in the trial, the 
vasectomised male partner with negative semen analysis at follow-up, should be the 
sole partner for that subject. 
†Note: Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of 
study participation) is only acceptable as true abstinence, i.e., when this is in line with 
the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial and withdrawal are not acceptable methods of contraception. 
Note: A female condom and a male condom should not be used together as friction between 
the 2 can result in either or both products failing. 
Note: Male patients with partners that are pregnant must use condoms to ensure that the fetus 
is not exposed to the Study Drug. 
6.3.2 
Other Requirements 
All patients will be required to fast for at least 10 hours before visits requiring fasted blood 
sampling.  Water and medications are not restricted during the fast, and the patient should ensure 
that they consume sufficient water in order to not become dehydrated. 
All patients will be encouraged to follow diet/life-style recommendations (Appendix E) during 
the study. 
7 STUDY DRUG 
7.1 
Study Drug Description 
Study Drug (ISIS 678354 or Placebo) characteristics are listed in Table 1. 
The Study Drug is contained in 2-mL stoppered glass vials.  The Study Drug and its storage and 
preparation instructions will be provided by the Sponsor or designee.  The Study Drug must be 
stored securely at 2-8 °Celsius and protected from light. 
ISIS 678354 vials contain 100 mg/mL olezarsen in Water for Injection.  Additionally, phosphate 
buffer and sodium chloride are added to control the pH of the solution and tonicity, respectively.  
The target pH is 7.4 and tonicity is within a physiologically acceptable range.  
Placebo vials contain 0.9% sodium chloride in Water for Injection.  Riboflavin is added for color 
similarity of placebo vials to olezarsen vials. 
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Table 1: 
Study Drug Characteristics 
Study Drug 
ISIS 678354 
Placebo 
Strength 
100 mg/mL 
Not Applicable 
Volume/Formulation 
0.8 mL solution per vial 
0.8 mL solution per vial  
Route of Administration 
Subcutaneous 
Subcutaneous 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with 
specific country regulatory requirements.   
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of Study 
Drug supplies provided by the Sponsor according to Sponsor instruction and in accordance with 
institutional policy. 
8 TREATMENT OF PATIENTS 
8.1 
Study Drug Administration 
For each individual patient, in the 50 mg cohort (Cohort A), Study Drug will be administered SC 
as a single 0.5 mL injection once every 4 weeks during Weeks 1-49 for a total of 13 doses.  For 
each individual patient in the 80 mg cohort (Cohort B), Study Drug will be administered SC as a 
single 0.8 mL injection once every 4 weeks during Weeks 1-49 for a total of 13 doses.  
Self-administration will be allowed after appropriate training of patient and/or caregiver. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
Study Drug (ISIS 678354 or placebo) preparation, administration, and patient observation 
post-Study Drug administration. 
8.2 
Other Protocol-Required Drugs 
No other Study Drug treatments are required by the protocol. 
8.3 
Other Protocol-Required Treatment Procedures 
No other treatment procedures are required by the protocol. 
8.4 
Treatment Precautions 
No specific treatment precautions are required. 
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8.5 
Safety Monitoring and Permanent Stopping Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
• For the purposes of safety monitoring and permanent stopping rules Baseline is 
defined as the average of the Day 1 pre-dose assessment and the last measurement 
prior to Day 1 
• In addition to the standard monitoring of clinical safety parameters, the following 
guidelines are provided for the monitoring of selected parameters chosen based on 
preclinical and clinical observations 
• In case of discrepancy between the test results from 2 sources, such as between the 
central and local lab, safety-mandated action must be initiated based on the more 
critical (lower or higher, as relevant) of the 2 values 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 
initial measurement) on new specimens.  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).   
Re-dosing Guidance:  In the event the initial laboratory result meets a stopping criterion, the 
results from the retest must be available and reviewed by a Medical Monitor prior to 
administration of the next dose of Study Drug (olezarsen or placebo).  In general, patients who 
do not meet the stopping rules based upon retest may continue dosing.  However, the 
Investigator and the Sponsor Medical Monitor (or designee) should confer as to at which dose 
Study Drug should be restarted, and whether additional close monitoring of the patient is 
appropriate.  If any of the permanently stopping criteria described below are met, the patient will 
be permanently discontinued from further treatment with Study Drug (olezarsen or placebo), 
evaluated fully as outlined below and in consultation with the Sponsor Medical Monitor or 
designee, and will be followed up in accordance with Section 8.8.of the protocol.  
The Investigator may interrupt or permanently discontinue study treatment for any medical 
reason including changes in clinical laboratory results. 
8.5.1 
Safety Monitoring and Permanent Stopping Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline, please refer to 
guidance above. 
All patients will have liver chemistry tests monitored monthly during the Treatment Period.  
Upon completion of the study Treatment Period, liver chemistry tests should be monitored 
during the Post-Treatment Follow-Up Period as per visit schedule in Appendix A.   
All routine liver chemistry test results will be reviewed on an ongoing basis at the safety review 
by the Sponsor Medical Monitor. 
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All lab alerts for abnormal liver chemistry tests must be promptly reviewed by the Investigator 
(within 2 business days of receipt) and Medical Monitor(s) according to the Medical Data 
Surveillance Plan. 
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 (ALT/AST) and total bilirubin should be tested as soon as 
possible (ideally within 3 days).  Testing at a lab that is local to the patient is permissible for this 
purpose. 
In the event of an ALT or AST measurement that is > 3 × ULN (or the greater of 
2 × baseline value or 3 × ULN if the baseline value was > ULN) at any time during the study 
(Treatment or Post-Treatment Period), and the initial measurement(s) is confirmed (as described 
in Confirmation Guidance above) the following steps should be taken: 
1. The Study Drug must be paused 
2. Liver chemistry tests (ALT, AST, alkaline phosphatase [ALP], INR and total bilirubin) 
retested at least once weekly until ALT and AST levels become ≤ 1.5 × ULN or 
1.5 × baseline if the baseline value was > ULN 
3. Further investigations into the cause of liver chemistry elevations should be performed. 
These may include the following evaluations*: 
a. Obtain a more detailed history of symptoms and prior and concurrent diseases 
b. Obtain further history for concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets 
c. Obtain a history for exposure to environmental chemical agents and travel 
d. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, cytomegalovirus 
(CMV) IgM, and EBV antibody panel) 
e. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA], and/ or anti-
smooth muscle antibody [SMA]) 
*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 or designee. 
4. Patients having alternative explanation for liver chemistry elevations may restart Study 
Drug at the original dose when ALT and AST levels become ≤ 3 × ULN (or below 2 × 
baseline if the baseline value was >ULN) and following consultation with the Sponsor 
Medical Monitor or designee who must assess that alternative etiology is well supported 
as the likely cause. 
5. Patients without alternative explanation for liver chemistry elevations but not yet meeting 
permanent Stopping Rules as described in bullet #6, must have Study Drug dose 
permanently reduced to 50 mg, if on an 80-mg dose (blinded olezarsen or placebo).  
Patients treated with 50-mg dose should remain on this dose.  
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6.  Patients without alternative explanation for liver chemistry elevations and meeting any 
of the following criteria must have Study Drug stopped permanently**; values that 
are not confirmed due to failure to retest or missing lab values will be presumed 
confirmed: 
• ALT or AST > 8 × ULN, which is confirmed 
• ALT or AST > 5 × ULN, which is confirmed and persists for ≥ 2 weeks 
• ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the 
baseline value was > ULN), which is confirmed and total bilirubin > 2 × ULN or INR 
> 1.5 
• ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the 
baseline value was > ULN), which is confirmed, and the new appearance (i.e., onset 
coincides with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or concomitant eosinophilia 
(> ULN) 
** The Investigator may decide to permanently stop Study Drug based on lesser changes in these 
parameters, taking into account all available and relevant data. 
8.5.2 
Safety Monitoring and Permanent Stopping Rules for Renal Function 
All patients will have renal function tests monitored monthly during the Treatment Period.  Upon 
completion of the study Treatment Period, renal function tests should be monitored during the 
Post-Treatment Follow-Up Period as per visit schedule in Appendix A. 
Renal function surveillance will include serum creatinine and urinalysis including UACR and 
UPCR.  The assessment of serum creatinine and urinalysis more frequently than monthly will be 
guided by the Sponsor Medical Monitor or designee. 
All renal function test results will be reviewed on an ongoing basis at the safety review by the 
Sponsor Medical Monitor or designee. 
All lab alerts for renal function tests must be promptly reviewed by the Investigator (within 
2 business days of receipt) and Medical Monitor(s) according to the Medical Data Surveillance 
Plan.  
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 (ideally within 3 days).  Testing at a lab that is local 
to the patient is permissible for this purpose. 
If any of the below criteria are met,  
• eGFR (by CKD-EPI formula) decrease from Baseline > 40% 
• UPCR > 1000 mg/g  
• UACR > 600 mg/g 
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and the initial measurement(s) is confirmed (as described in Confirmation Guidance above) the 
following steps should be taken: 
1. The Study Drug must be paused 
2. Further investigations into the cause of renal function abnormalities should be performed. 
These may include review of patient’s prior and concurrent diseases and procedures, 
concomitant medications for potentially nephrotoxic agents, and search for potential 
pre-renal causes. 
3. Patients having alternative etiology identified that may account for abnormal renal results 
may restart treatment with Study Drug when: 
a. Lab values have improved to: 
− eGFR decrease < 40% from baseline, and/or  
− UPCR < 1000 mg/g, and/or 
− UACR < 600 mg/g, and 
b. Study Medical Monitor or designee has approved Study Drug treatment to restart 
4. Patients without identified alternative etiology for renal function abnormalities may 
restart Study Drug Treatment when: 
a. Lab values have improved to: 
− eGFR decrease < 20% from baseline, and/or  
− UPCR < 500 mg/g, and/or 
− UACR < 300 mg/g, and 
b. Study Medical Monitor or designee has approved Study Drug treatment to restart 
5. Patients without alternative explanation for renal function abnormalities and meeting any 
of the following criteria must have Study Drug stopped permanently*; values that are 
not confirmed due to failure to retest or missing lab values will be presumed confirmed: 
• eGFR (by CKD-EPI formula) decrease from Baseline >50%   
• UPCR > 2000 mg/g 
• UACR > 1200 mg/g 
* The Investigator may decide to permanently stop Study Drug based on lesser changes in these 
parameters observed in isolation or in association with other renal-related abnormalities, taking 
into account all available and relevant data. 
8.5.3 
Safety Monitoring and Permanent Stopping for Platelet Count Results 
All patients will have PLT counts monitored monthly during the Treatment Period.  Upon 
completion of the study Treatment Period, PLTs will be monitored as per visit schedule in 
Appendix A. 
All PLT count results must be reviewed promptly (within 2 business days of receipt) by the 
Investigator or the designee to ensure that the count has not met a dose interruption or stopping 
rule.  Actions to be taken in the event of reduced PLT count are shown in Table 2. 
 
 
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Table 2: 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Study Drug  
Monitoring 
≥ 100K/mm3 
No action 
Monitor every month 
Below values to be 
confirmed ideally 
within 3 days but no 
later than 7 days 
If PLT count is confirmed, 
follow dosing guidance 
below1: 
If PLT count is confirmed, follow 
monitoring guidance below1: 
≥ 75K to < 100K/mm3 
Discussion with Medical 
Monitor3 
Closer observation; monitor every 
2 weeks2 
≥ 50K to < 75K/mm3 
Pause dosing.  When 
≥ 2 successive PLT count 
values return to ≥ 75K/mm3 
restart dosing only if approved 
by Medical Monitor3 
Closer observation 
Monitor every 2-3 days until 2 successive 
values show improvement 
Consider discontinuation of anticoagulants/ 
antiplatelet agents/non-steroidal 
anti-inflammatory drug (NSAIDs) 
≥ 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 anticoagulants/antiplatelet 
agents/, NSAIDs, while PLT count 
˂ 50K/mm3 if possible 
Platelet panel to be drawn (Table 3) 
˂ 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 and/or IVIG recommended1,4 
Consider referral to hematologist  
Discontinue anticoagulants/antiplatelet 
agents/NSAIDs medication while PLT 
count ˂ 50K/mm3 if possible 
Platelet panel to be drawn (Table 3) 
1 Recommended if platelet count decrease / thrombocytopenia cannot be explained by other reasons and is therefore considered 
drug related. 
2 Once a patient commences every 2-week monitoring this frequency of monitoring should continue until the platelet count 
returns to ≥ 100K/mm3 for 2 successive values. 
3 The suitability of the patient for reduced (from blinded olezarsen/placebo 80 mg to 50 mg), interrupted and/or continued dosing 
will be determined by the Investigator in consultation with the Medical Monitor and will be based on factors such as the 
original rate of decline in the patient’s PLT count, whether any bleeding events were experienced by the patient, and the speed 
of recovery of PLT count after interruption of dosing. 
4 Recovery in platelet count may be accelerated by administration of high-dose glucocorticoids.  Treatment as recommended by 
the American Society of Hematology (ASH) (2019) guidelines for immune thrombocytopenia (Blood Advances, 
10 DECEMBER 2019, Volume 3, Number 23) includes initial therapy with either dexamethasone 40 mg per day for 4 days, or 
prednisone 0.5 to 2.0 mg/kg per day.  Prednisolone or prednisone may be administered for up to 2 to 4 weeks with taper; 
alternatively, intravenous immunoglobulin (IVIG) may be administered at 0.4 g/kg/d for 5 days, or infusions of 1 g/kg/d for 
1-2 days (Provan et al. 2010; Provan et al. 2019).  
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Any case of a confirmed PLT count reduction to levels below 50,000/mm3 accompanied by a 
MB event or CRNMB event, or PLT count of < 25,000/mm3 independent of a MB or CRNMB 
event, is considered an adverse event of special interest (AESI) and should be reported following 
the same requirements as for SAE reporting (Section 9.4.1). 
The following (Table 3)  is a list of lab analyses that should be performed for any patient with an 
occurrence of confirmed PLT count less than 50,000/mm3 during this study.  Archived samples 
prior to Day 1 of investigational treatment may also be analyzed in order to determine the 
patient’s baseline conditions. 
Table 3: 
Platelet Panel 
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 
EDTA sample for PLTs 
To Be Performed at Central Lab 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes and mean platelet volume 
Total globulins:  IgG and IgM 
Complement:  total C3, total C4, C5a 
Serology for:  HBV, HCV, HIV  
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies 
Anti-ASO antibody 
Note:  In addition, these labs may also be performed in the event of a platelet count less than 75,000/mm3 after 
discussion with the Study Medical Monitor.  Additional lab tests may be considered in order to ascertain potential 
causative conditions for significant platelet count decreases / thrombocytopenia. 
 
8.5.4 
Safety Monitoring and Permanent Stopping Rules for Bleeding Events 
Patients 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.  All bleeding events are 
considered AEs and reported on the AE case report form. 
If a  MB or CRNMB event occurs (as defined below), the Investigator must notify the Medical 
Monitor (or designee) and the patient should be treated, as needed, immediately and closely 
monitored (vital signs, lab tests such as hemoglobin (Hb), hematocrit (HCT), and PLT count, 
additional visits, overnight stays and coagulation tests may be needed if deemed appropriate by 
the treating physician) throughout the Treatment and Post-Treatment Evaluation Periods and an 
(S)AE case report form will be completed.  In addition, approximately 2 mL of K2EDTA 
anticoagulated blood will be collected and resulting plasma must be stored allowing for a 
centralized assessment of olezarsen concentrations. 
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If a minor bleeding event occurs, the Investigator should notify the Medical Monitor (or 
designee) and additional testing of coagulation parameters (aPTT, PT, INR), PLT count, and 
PLT volume may be performed. 
Major bleeding is defined as 1 of the following (Schulman and Kearon 2005): 
1. Fatal bleeding 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or 
intramuscular with compartment syndrome 
3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed RBCs or whole 
blood or a fall in Hb of 2.0 g/dL (1.24 mmol/L) or more within 24 hours 
Clinically relevant non-major bleeding is defined as any sign or symptom of hemorrhage 
(e.g., more bleeding that would be expected for a clinical circumstance, including bleeding found 
by imaging alone) that does not fit the criteria for MB but does meet at least 1 of the following 
criteria (Kaatz et al. 2015): 
1. Requiring medical intervention by a healthcare professional 
2. Leading to hospitalization or increased level of care 
3. Prompting a face to face (i.e., not just a telephone or electronic communication) 
evaluation 
Minor bleeding events are those that do not fulfill the criteria for MB or CRNMB events (defined 
above), for example excess bruising, petechiae, gingival bleeding on brushing teeth. 
In the event of MB or CRNMB as assessed by the Investigator, and in the absence of any 
alternative explanation for the cause of bleeding dosing of a patient with Study Drug 
(olezarsen or placebo) may be interrupted or stopped permanently.  The follow-up schedule 
for any events meeting this stopping criterion will be determined, including the suitability of the 
patient for resumption of dosing by the Investigator in consultation with the Medical Monitor (or 
designee). 
8.5.5 
Safety Monitoring for Constitutional Symptoms 
Patients 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.  Patients who 
experience persistent or increasing symptoms should be tested for ADA and discussed with the 
Medical Monitor or designee to determine whether additional monitoring or laboratory tests are 
required. 
8.5.6 
Safety Monitoring for Potential Hypersensitivity Reactions 
Patients will be instructed to promptly report any signs or symptoms of potential hypersensitivity 
reactions including:  urticarial rash, pruritus, flushing, angioedema, dyspnea, and/or acute onset 
hypotension, that may arise during the study.  The Investigator should closely evaluate all 
potential causes, including concomitant illnesses.  Patients who experience symptoms of a 
potential hypersensitivity reaction should be tested for ADA and be discussed with the Medical 
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Monitor or designee to determine whether additional monitoring or laboratory tests are required.  
If a hypersensitivity reaction is established, study drug discontinuation should be recommended.  
The patient’s symptoms should be managed per standard of care. 
8.5.7 
Safety Monitoring for Triglyceride and Apolipoprotein B Elevations 
Triglycerides (TG) will be monitored for safety every 3 months.  If the measured triglyceride 
level either (a) in patients with Baseline TGs < 500 mg/dL subsequently exceeds 880 mg/dL or 
(b) in patients with Baseline TGs ≥ 500 mg/dL and < 2000 mg/dL subsequently exceeds 
2000 mg/dL and increases by at least 10% from Baseline or (c) in patients with Baseline TGs 
≥ 2000 mg/dL subsequently increases by at least 30% from Baseline, the site will be notified to 
contact the patient by phone as soon as able, and no later than their next monthly visit or phone 
call, to counsel the patient on dietary, lifestyle and medication compliance, and educate and 
assess the patient for signs and symptoms of pancreatitis.  To maintain the blind, the same 
notification will be provided for an additional patient in the other treatment group using 
pre-defined criteria to balance the frequency of alerts for both treatment groups, active and 
placebo.  If the TG value remains persistently high at the next regularly scheduled TG safety 
assessment, a qualified individual, ideally not associated with that subject’s assessment, will be 
informed of the TG value to evaluate and manage the patient’s TG levels, moving forward 
throughout the study, ideally independent of the Investigator’s and Study Coordinator’s 
knowledge.  
Given the potential for LPL inhibition to change the distribution of cholesterol on lipoproteins, 
without necessarily affecting the number of cholesterol-rich lipoproteins, apoB levels rather than 
LDL-C levels will be monitored for safety at 6 months then every 3 months, consistent with 
guidelines which recognize apoB as the optimal atherogenic lipid metric (Mach et al. 2020).  If 
the measured apoB level increases by ≥ 20 mg/dL, the site will be notified to counsel the patient 
at their next monthly visit on lifestyle and medication compliance.  To maintain the blind, the 
same reminder will be provided for an additional patient in the other treatment group, using 
pre-defined criteria to balance the frequency of alerts for both treatment groups, active and 
placebo.  If the subsequent measurement is still high, then the Investigator will be informed of 
the apoB value and if clinically indicated based on local SOC, may adjust background lipid 
lowering therapy, in consultation with the patient, according to patient’s ASCVD risk.  
8.6 
Adjustment of Dose and/or Treatment Schedule 
Dose adjustments for PLT count reduction must be made in accordance with Table 2 (above). 
Other adjustments, including dose interruptions, and/or decreasing the dose will be allowed for 
safety or tolerability after consultation with the Sponsor Medical Monitor or designee. 
Dose adjustments should not occur unless absolutely necessary prior to Week 25. 
8.7 
Discontinuation of Study Drug Administration 
Reasons for permanent discontinuation of Study Drug administration are:  
• The patient experiences an AE that necessitates permanent discontinuation of Study 
Drug  
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− At the discretion of the Investigator due to a safety concern 
− At the patient’s request due to an adverse event 
− The patient develops laboratory test abnormalities that meet any of the stopping 
rules listed in Section 8.5 
− The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• Reasons not related to an AE 
− Patient request to stop Study Drug but continue study participation 
− The patient withdraws consent for study participation 
− Investigator decision (e.g., non-compliant patient)  
− Sponsor decision  
The reason for discontinuation of Study Drug must be recorded in the eCRF and source 
documentation.  If the Investigator decides that discontinuation of Study Drug is warranted, the 
Investigator should make every effort to contact the Sponsor or TIMI Hotline prior to 
discontinuation of Study Drug. 
Patients who had Study Drug administration discontinued for any reason other than full 
withdrawal of consent for study participation should continue their participation in the study, 
attending visits and procedures as per Section 8.7.1, if possible, and providing survival status by 
the end of the trial.  If the patient declines or is unable to attend study visits, the Investigator 
should clarify what type of follow-up the patient is agreeable to:  in person, by phone/mail, 
through family/friends, via correspondence/communication with other physicians, and/or from 
review of the medical records, and as allowed per local regulations.  Wherever possible these 
patients should continue to be followed up via the agreed means to collect information on AE, 
concomitant medications and survival status.  At the very least, the patient’s status at the end of 
the Treatment Period should be ascertained and documented wherever possible.  The agreed 
means of follow-up will be documented in the patient records and notified to the Sponsor. 
8.7.1 
Follow-up Visits for Early Termination from Treatment Period or 
Post-Treatment Follow-up Period 
If a patient discontinues early from the Treatment Period, treatment early termination (Tx-ET) 
visit assessments should be performed 4 weeks from the last dose of Study Drug, and patients 
should start the 13-week Post-Treatment Follow-up Period to collect the study assessments in 
accordance with the Schedule of Procedures in Appendix A.  Patients should also be strongly 
encouraged to attend remaining landmark visits at Weeks 25 and 27, as well as at Weeks 51 and 
53 (calculated based on the time elapsed since Day 1) to collect fasting lipid panels and conduct 
safety assessments in accordance with Appendix A.  Depending on the day of discontinuation, 
follow-up visits and landmark visits may overlap and can be combined.   
Any patient who chooses to discontinue early from the Post-Treatment Follow-up Period should 
be strongly encouraged to complete safety procedures and observations in accordance with 
Appendix A.  If the patient declines or is unable to participate in the above, final post-treatment 
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early termination (Post-Tx ET) assessments should be performed at the time of withdrawal in 
accordance with Appendix A. 
8.8 
Withdrawal of Patients from the Study Procedures 
A participant may withdraw from the study at any time at his/her own request.  Patients should 
be encouraged to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix A).  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. 
Full withdrawal of consent:  Any patient who provides full withdrawal of consent to participate 
in the study will be removed from further treatment and study observation immediately upon the 
date of request. 
If a participant withdraws consent from the study, he/she may request destruction of any 
remaining samples taken and not tested, and the Investigator must document any such requests in 
the site study records and notify the Sponsor accordingly. 
If the participant withdraws consent for disclosure of future information, no further evaluations 
should be performed, and no additional data should be collected.  The Sponsor may retain and 
continue to use any data collected before such withdrawal of consent.  In participants who 
request to prematurely stop Study Drug and study-related procedures, collection of adverse 
events and clinical endpoints will continue as permitted by local laws and regulations, unless the 
participant requests otherwise. 
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved. 
Publicly available information should be used to determine vital status (whether the participant is 
alive or dead) as permitted by local law. 
8.8.1 
Lost to Follow-up 
To prevent participants being lost to follow-up, their contact details, including next of kin 
contacts, should be collected initially and updated regularly by the site staff or representative.  
The Investigator should educate the participant on the importance of contact with the 
Investigator throughout the study. 
Repeated attempts will be made to locate and obtain pertinent medical information for 
participants who are initially lost to follow-up.  A participant will be classified as lost to follow-
up only if he/she has failed to return for the required study visits and his/her vital status remains 
unknown at the end of the study despite multiple attempts to contact him/her via telephone, fax, 
email, certified letter, or through patient locator agencies (if allowed by national regulation).  
Where permissible by local law, the Informed Consent Document will include language to grant 
the option to employ outside companies to assist in obtaining updated contact information or 
ascertainment of vital status of lost participants using publicly available source. 
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8.9 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
8.9.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including OTC 
medications, herbal medications and vitamin supplements) administered from the time the 
patient has signed the informed consent at Screening to the end of the Post-Treatment Follow-up 
Period. 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
Study patients are prohibited from receiving other experimental agents during the study.  This 
includes marketed agents at experimental dosages that are being tested for the treatment of 
hypertriglyceridemia. 
Patients should consult with the Investigator or designee prior to initiating any new medication, 
including non-prescription or herbal compounds or any other non-drug therapy.  If a disallowed 
concomitant therapy is administered, the study Investigator must discuss with the Medical 
Monitor / TIMI whether Study Drug may continue.  Regardless of the decision regarding Study 
Drug continuation, all other study procedures and follow-up should continue as described in the 
protocol. 
8.9.2 
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 Follow-up Period. 
Disallowed Concomitant Procedures 
Plasma apheresis is not allowed during the study. 
8.10 
Treatment Compliance 
At each applicable dosing visit, patients may be administered study drug by a delegated study 
staff member.  The study drug administration and compliance will be documented as per the 
protocol, Study Drug Manual, and captured in the electronic data capture system.  If study drug 
is administered by a home healthcare professional, source documentation will be completed and 
provided to the site to document the details of study drug administration.  If study drug is 
self-administered, after appropriate training of patient and/or caregiver, site staff will record the 
study drug administration details via contact with the patient.   
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9 SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the applicable Ionis and/or designee SOPs throughout the conduct of the clinical 
trial. 
9.2 
Regulatory Reporting Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of SAEs including SUSARs per the ICH guidelines E2A and ICH GCP.  
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 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 all reported SAEs and 
determine if there is a reasonable possibility that the Study Drug (ISIS 678354 or placebo) is 
causally related to a reported SAE.   
The Sponsor or designee will evaluate the available information for all reported SAEs and decide 
if there is a reasonable possibility that the Study Drug (olezarsen or placebo) caused the SAE 
and, therefore, 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 in accordance with EC Clinical trials Directive 2001/20/EC or as 
per national regulatory requirements in participating countries. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
medicinal (investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An adverse event can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
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• Recurrence of an intermittent medical condition (e.g., headache) not present at 
Baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from Study Drug 
• Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive procedures 
such as biopsies) 
9.3.2 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered ADR. 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the adverse event has been determined by the Sponsor as at least a 
reasonable possibility, i.e., the relationship cannot be ruled out. 
Suspected Unexpected Adverse Drug Reaction  
A suspected unexpected ADR is any ADR, the nature or severity of which is not consistent with 
the applicable product information, e.g., Investigator's Brochure for an unapproved medicinal 
(investigational) product. 
A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A SAE 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 
Note:  An AE or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the Investigator or Sponsor, its occurrence places the patient at 
immediate risk of death.  It does not include an AE or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• 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 patient (whether 
the patient is male or female) 
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• Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent 1 of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room (ER) or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, the development of drug dependency or 
drug abuse, or spontaneous abortion/miscarriage 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE]; OR Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials; the 
event itself may be of relatively minor medical significance (such as severe headache without 
any further findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on 
the eCRF. 
9.3.4 
Adverse Event of Special Interest  
An adverse event of special interest (AESI), including both serious or non-serious events is one 
of scientific and medical concern specific to the Sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the Investigator to the Sponsor may be 
appropriate. 
Adverse events of special interest are required to be reported by the Investigator to the Sponsor 
following the same requirements as for SAE reporting (Section 9.4.1). 
For the purpose of this study there are 2 AESIs: 
1. Severe reductions in PLT count < 50,000/mm3 accompanied by a MB event or CRNMB 
event, or PLT count of < 25,000/mm3 independent of a MB or CRNMB event. 
2. Requirement of any use of medications (such as antihistamines, acetaminophen, 
non-steroidal anti-inflammatory drugs [NSAIDs], corticosteroids, etc.) as pre-treatment 
to avoid a hypersensitivity reaction or recurrence of a previous hypersensitivity reaction. 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible.  Before a 
diagnosis is confirmed, all symptoms should be reported as separate AEs. 
9.4.1 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs and 
AESIs (regardless of their relationship to Study Drug) should be reported to the Sponsor or 
designee immediately, without undue delay, but no later than within 24 hours of the Study 
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Center’s first knowledge of the event.  The collection of SAEs will begin after the patient signs 
the informed consent form and stop at the end of the patient’s Follow-up Period.  SAEs should 
be captured and reported electronically within Electronic Data Capture System (EDC).  The SAE 
reporting instruction, including the fax number and email address can be found in the 
Investigator site file for the study. 
Detailed information should be actively sought and included on electronic Adverse Event Forms 
in EDC as soon as additional information becomes available.  All SAEs will be followed until 
resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up visit 
will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s Follow-up Period.  The Investigator will monitor each 
patient closely and record all observed or volunteered AEs on the Adverse Event Case Report 
Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form.   
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (olezarsen or placebo) is characterized by 1 of the 
following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug, 
e.g., confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug (olezarsen 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 678354 or placebo) administration and/or exposure 
suggests that a causal relationship is unlikely (For reporting purposes, 
Unlikely/Remote will be grouped together with Not Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator 
believes no relationship exists between the event and Study Drug 
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9.4.3.2 
Severity 
The severity of AEs and SAEs relating to laboratory tests will be graded based on criteria from 
the CTCAE Version 5.0, November 2017 (refer to Appendix D).  Any AE not listed in 
Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s 
usual daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
The severity of AEs and SAEs relating to AEs at the injection site will be graded based on 
criteria from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials, Sept 2007 (refer to Appendix D).   
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 (olezarsen or placebo) due to the event is characterized by 1 of the 
following. 
• None:  No changes were made to Study Drug (olezarsen or placebo) administration 
and dose 
• Not Applicable:  SAE/AE was reported during Screening Period prior to Study Drug 
administration 
• Permanently Discontinued:  Study Drug was discontinued and not restarted 
• Temporarily Interrupted, Restarted - Same Dose:  Dosing and/or dosing 
frequency was temporarily interrupted/changed or delayed due to the AE and 
restarted at the same dose 
• Reduced Dose:  Dosing was reduced to a lower dose  
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form.  Treatment should also be recorded on the concomitant 
treatment or ancillary procedures eCRF, as appropriate. 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
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• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF 
(the SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should 
be entered as the SAE resolution date) 
• Recovered with Sequelae:  The signs/symptoms of the reported SAE have improved 
but not completely resolved, and a new baseline for the patient is established since 
full recovery is not expected 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
• Unknown:  The outcome of the reported SAE is not available, e.g., patient is lost to 
follow-up 
9.4.3.6 
Follow-up of Adverse Event 
Investigator Follow-Up 
During the Study Period, the Investigator should follow each AE until the event has resolved to 
baseline grade or better, the event is assessed as stable, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all SAEs considered to be 
related to Study Drug or related to study procedures until a final outcome can be reported. 
Resolution of AE (with dates) should be documented on the Adverse Event eCRF and in the 
patient’s medical record to facilitate source data verification.   
Investigator should follow-up or support the Sponsor’s effort to follow up with all pregnancies 
reported during the study from either the study patient or the female partner of male study patient 
until pregnancy outcome is available.   
Sponsor Follow-Up 
For SAEs, AESI and pregnancy cases in patients who have completed or terminated the study, 
the Sponsor or a designee should follow-up by telephone, fax, email, and/or a monitoring visit 
(on-site or remote access) to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
9.4.3.7 
Adjudication Committees 
All AEs and SAEs that occur during the study that are consistent with MACE will be adjudicated 
by a blinded, independent MACE-Adjudication Committee (MACE-AC) as outlined in the 
MACE Adjudication Charter. 
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MACE-AC will adjudicate all fatal events and events suggestive of non-fatal myocardial 
infarction, hospitalization for unstable angina, hospitalization for (worsening) heart failure, 
coronary and non-coronary revascularization procedures, and stroke.  The criteria used by the 
MACE-AC to determine the occurrence of any of the events will follow the recommendations 
included in published Cardiovascular and Stroke Endpoint Definitions for Clinical Trials (Hicks 
et al. 2018; Thygesen et al. 2018). 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for episodes of acute pancreatitis or suspected 
pancreatitis in the 5 years prior to enrollment will be collected by review of each patient’s 
medical chart and these events will also be adjudicated. 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the patient’s 
consent to participate in the study 
• The condition that required the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the opinion 
of the Investigator between the patient’s consent to participate in the study and the 
timing of the procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
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9.5.3 
Dosing Errors 
Study Drug (olezarsen or placebo) errors (for example, overdose, underdose, and administration 
error) should be reported as a medication error on the Protocol Deviation CRF and an AE CRF, 
if applicable.  A brief description should be provided when reporting the deviation, including 
whether the patient was symptomatic (list symptoms) or asymptomatic, and whether the event 
was accidental or intentional. 
Dosing details should also be captured on the Dosing Case Report Form.  If the patient takes a 
dose of Study Drug that exceeds protocol specifications and the patient is symptomatic, then 
each symptom should be documented as an AE and be reported per Section 9.4. 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied.  An overdose or incorrect administration of study treatment is not itself an adverse 
event, but it may result in an adverse event.  All adverse events associated with an overdose or 
incorrect administration of Study Drug should be recorded on the Adverse Event eCRF.  The 
event should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning 
of the event). 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1.   
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, or within 30 weeks of the last dose of study 
drug, 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 of 
awareness of the pregnancy outcome. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility.   
Female patients:  If a suspected pregnancy occurs while on the study (including during the 
Follow-up Period), a pregnancy test will be performed.  The patient with a confirmed pregnancy 
will be immediately withdrawn from treatment with Study Drug.  However, the patient will be 
encouraged to complete the post-treatment follow-up portion of the study to the extent that study 
procedures do not interfere with the pregnancy.  Regardless of continued study participation, the 
Investigator will assist the patient in getting obstetrical care and the progress of the pregnancy 
will be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, 
or spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records to obtain additional 
information relevant to the pregnancy progress and outcome.  A longer follow-up may be 
required if the newborn child experiences a medical condition.  Follow-up will be performed to 
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the extent permitted by the applicable regulations and privacy considerations, e.g., pregnancy 
ICF may be required. 
Male patients:  The progress of the pregnancy of a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
follow-up with the mother and may request access to the mother and infant’s medical records to 
obtain additional information relevant to the pregnancy progress and outcome.  A longer 
follow-up may be required if the newborn child experiences a medical condition.  Follow-up will 
be performed to the extent permitted by the applicable regulations and privacy considerations, 
e.g., partner ICF may be required.  
Spontaneous abortion/miscarriage is to be reported as an SAE.  See Section 9.4.1 for additional 
information regarding SAE reporting. 
10 STATISTICAL CONSIDERATIONS 
10.1 
Stratification, Subsets, and Covariates   
The stratification factor is: 
• TG ≥ 500 mg/dL (5.65 mmol/L) vs. < 500 mg/dL at Qualification 
Subgroup analysis for primary and secondary endpoints will include, but not be limited to, 
baseline TG ≥ 500 mg/dL vs. < 500 mg/dL, age group, race, sex, BMI, diabetes status, baseline 
HbA1c, use of baseline background lipid-modifying therapy versus none, statins versus no 
statins, previous treatment with Volanesorsen.  Details of the subgroup analyses will be provided 
in the SAP. 
In general, the covariate will include the stratification factor and baseline measurements (where 
applicable), the details are provided in Section 10.6.3. 
10.2 
Sample Size Considerations 
With 33 patients in each olezarsen treatment group and 22 in the pooled placebo group, there 
would be an approximately 80% power to detect a 60% difference between each olezarsen 
treatment group and pooled placebo group at an alpha level of 0.05 (two-sided), assuming 60% 
reduction in the olezarsen treatment patients, no change in the placebo patients, and a common 
SD of approximately 73%.  It is estimated that dropout rate is approximately 20%.  
Approximately 152 patients will be enrolled in this trial to account for potential early dropouts 
and to facilitate general safety evaluations.  
10.3 
Populations 
Full Analysis Set:  All patients who are randomized and received any amount of Study Drug 
(olezarsen or placebo).  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. 
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Per Protocol Set (PPS):  Subset of the FAS who received at least 5 monthly doses of Study Drug 
within the first 6 months of the Treatment Period, have a baseline fasting TG assessment, and 
who have no significant protocol deviations that could compromise the interpretation of efficacy.  
Significant deviations will be determined prior to unblinding for statistical analysis.  This 
population will be used for supportive inferences concerning efficacy.  
Safety Set:  All patients who are randomized and receive any amount of Study Drug.  This 
population will be used for all safety analyses. 
PK Population:  All patients who are randomized and receive any amount of olezarsen 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, Month 6 and Month 12 
Baseline PLT is defined as the average of all non-missing pre-dose assessments. 
Baseline lipid measurements are defined as the average of the pre-dose measurement on Day 1 
and all measurements from the Qualification Period. If the Day 1 pre-dose and Qualification 
Period measurements are all missing, then the last non-missing measurement from the Screening 
Period will be used as baseline. 
Baseline for other measurements is defined as the last non-missing assessment prior to the first 
dose of Study Drug.  
The Month 6 lipid assessments are defined as the average of Weeks 25 and 27 fasting 
assessments.  The Month 12 lipid assessments are defined as the average of Weeks 51 and 53 
fasting assessments.  For both Month 6 and Month 12, if 1 of the 2 assessments is missing, then 
the non-missing assessment will be used. 
10.5 
Interim Analysis and Multiplicity 
10.5.1 
Unblinded Interim Safety Analysis 
An unblinded interim safety analysis will not be conducted. 
10.5.2 
Multiplicity for the Final Efficacy Analysis 
The multiplicity will be controlled by using a hierarchical ranking strategy in the following 
testing sequence.  All tests will be conducted at a two-sided alpha level of 0.05.  If any test is not 
statistically significant, the test(s) at the lower rank will be considered exploratory. 
1. Primary endpoint:  Comparison of percent change in fasting TG from Baseline to Month 
6 between olezarsen 80-mg treatment group and pooled placebo group in the FAS 
2. Primary endpoint (not co-primary endpoint):  comparison of percent change in fasting TG 
from Baseline to Month 6 between olezarsen 50-mg treatment group and pooled placebo 
in the FAS. 
3. Secondary endpoints:  the testing sequence for the secondary endpoints will be specified 
in the SAP.   
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• Comparison of percent change in fasting TG from Baseline to Month 12 between 
each olezarsen treatment group and pooled placebo group in the FAS 
• Comparison of proportion of patients who achieve fasting TG < 150 mg/dL 
(1.69 mmol/L) at Month 6 and proportion of patients who achieve fasting TG 
< 150 mg/dL at Month 12 between each olezarsen treatment group and pooled 
placebo group in the subgroup of FAS with baseline TG < 500 mg/dL 
• Comparison of proportion of patients who achieve fasting TG < 500 mg/dL 
(5.65 mmol/L) at Month 6 and proportion of patients who achieve fasting TG 
< 500 mg/dL at Month 12 between each olezarsen treatment group and pooled 
placebo in the subgroup of FAS with baseline TG ≥ 500 mg/dL 
• Comparison of percent change in fasting apoC-III, VLDL-C, remnant cholesterol, 
non-HDL-C, HDL-C, TC, apoB, LDL-C, and apoA-1 from Baseline to Month 6 and 
Month 12 between each olezarsen treatment group and pooled placebo group in the 
FAS 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, and any outcomes derived from the data will be provided in the 
patient listings.  Patient data listings will be presented for all patients enrolled into the study.  
Descriptive summary statistics including n, mean, median, SD, 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. 
All primary and secondary endpoints will be assessed on the FAS and PPS, with the former 
being the basis for the primary efficacy analysis.  All safety assessments will be performed on 
the Safety Set. 
Any deviation(s) from the planned analyses will be described and justified in the final clinical 
study report. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The patient disposition will be summarized by treatment group.  All patients 
enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug (olezarsen or placebo) received will be 
summarized by treatment group.   
Patient incidence rates of 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 678354 or placebo) will be summarized by the 
Medical Dictionary for Regulatory Activities (MedDRA™) system organ class, and by 
MedDRA™ term.  A treatment-emergent AE is defined as any event not present prior to the 
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initiation of the Study Drug or any event already present that worsens following initiation of the 
Study Drug.  
Tables and/or narratives of treatment emergent deaths, serious and significant AEs, including 
early withdrawals due to AEs, will also be provided. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count with 
differential, coagulation panel, 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 678354 or placebo) administration, as appropriate.  In addition, the 
number of patients who experience abnormalities in clinical laboratory evaluations will be 
summarized by treatment group. 
Vital sign and ECG measures will be tabulated by treatment group.  
10.6.3 
Efficacy Analysis 
10.6.3.1 Analysis of Primary Endpoint 
The primary analysis of the primary endpoint is to compare the percent change from Baseline to 
Month 6 in fasting TG between each olezarsen treatment group vs. pooled placebo group using 
an ANCOVA model in the FAS.  The ANCOVA model will include the effects of treatment 
(olezarsen 80 mg, olezarsen 50 mg, or Placebo), and log-transformed baseline TG.  If patients 
have intercurrent event(s) before Week 25, e.g., treatment discontinuation, use of additional 
medication, changes in background or concomitant treatments, the Treatment Policy strategy will 
be implemented, the patients’ assessments post intercurrent events will continue to be collected.  
The missing TG value at Months 6 or 12 will be imputed using an imputation model that 
contains the following variables: baseline fasting TG, fasting TG at each post-baseline visits and 
the multiple imputation will be stratified by treatment group (Schafer 1997; Schafer 1999).  
The MCMC method will be used under the multivariate normality assumption to impute the 
missing values by treatment group.  To conform to the multivariate normality assumption, 
baseline and post-baseline TG will be natural log-transformed before the imputation process, the 
data will be back transformed to create the imputed data set after the imputation.   
The primary efficacy analysis will take place after the last patient has completed the Week 53/ET 
visit and the database has been locked.  Details of the controlled access to the unblinded data will 
be outlined in the SAP and Unblinding Plan. 
The following sensitivity analyses of the primary endpoint will be conducted to assess the 
robustness of the primary analysis result, and details of the analyses will be outlined in the SAP: 
• The primary analysis described above will be repeated in the PPS. 
• The primary analysis will be repeated in the subset of FAS with no missing TG value 
at baseline and Month 6. 
• A nonparametric Wilcoxon rank-sum test will be performed on the percent change in 
TG from baseline to Month 6.  Missing data will be handled using the same multiple 
imputation method as the primary analysis.  The treatment difference will be assessed 
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using the Hodges-Lehmann estimator of the location shift and corresponding 95% CI.  
The analysis will be conducted in the FAS. 
• A two-dimensional tipping-point analysis will be conducted on the imputed data 
(based on the primary imputation approach as described above) to assess the 
influence of missingness on the conclusion of the treatment difference.  A range of 
penalties will be added to the imputed values for each group until the result becomes 
non-significant and tipping points are identified.  The analysis will be conducted in 
the FAS. 
• A few sensitivity analyses using controlled imputations (pattern mixture models 
(PMM)) with ANCOVA similar to that for primary analysis will be conducted in the 
FAS to assess the robustness of the primary analysis results.  With these approaches, 
missing not at random (MNAR) is assumed and the mean function for the missing 
data from patients treated with olezarsen who discontinue the study is pre-specified in 
ways that assess the robustness of the missing at random (MAR) assumption in the 
primary analysis. 
− Patients with missing TG value at Month 6 will be imputed using a pattern 
mixture model.  Specifically, for patients treated with olezarsen who discontinue 
the study due to AE or lack of efficacy (i.e., informative missing), their missing 
TG data after treatment discontinuation will be multiply imputed using the copy 
increment from reference (CIR) approach based on the estimates from of the 
placebo patients.  The CIR approach is detailed in (Carpenter et al. 2013).  The 
assumption is when a patient discontinues treatment due to informative missing, 
from discontinuation onwards he/she would progress in the same way as the 
patients in the placebo group.  For patients who discontinue due to other reasons 
and all patients from the placebo group, their missing data will be treated as 
non-informative missing, and data will be multiply imputed based on the 
distribution of their own arm.  The analysis will be conducted in the FAS.  
Baseline and post-baseline TG will be natural log-transformed before the 
imputation process, the data will be back transformed to create the imputed data 
set after the imputation. 
− All patients treated with olezarsen who discontinue the study will have missing 
post-treatment discontinuation TG values multiply imputed using the CIR 
approach based on the estimates from the placebo patients.  Missing TG for 
placebo patients will be imputed using the same multiple imputation method as 
the primary analysis 
− Patients with missing TG values after treatment discontinuation will have TG 
values multiply imputed based on the known assessments from the retrieved 
dropouts (e.g., for Month 6, the retrieved dropouts include those patients who 
discontinue treatment before Week 25 but still have assessments at Week 25 or 
27), if there are a sufficient number of retrieved dropouts.  The imputation model 
will include the following variables:  fasting TG values at baseline and 
post-baseline visits and the multiple imputation will be stratified by treatment 
group.  If there is no sufficient number of retrieved dropouts, missing TG value 
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after treatment discontinuation at Month 6 or Month 12 will be imputed using a 
“wash-out” (Jump to Reference, J2R) multiple imputation approach.  With the 
approach, patients treated with olezarsen who discontinue study will have 
missing post-discontinuation TG values multiply imputed based on baseline 
fasting TG and history of pancreatitis (yes/no) of the patient, and the imputation 
model for the placebo group.  Patients in the placebo group who discontinue the 
study will have missing post-treatment discontinuation TG values multiply 
imputed using the MI method as the primary analysis.  Baseline and 
post-baseline TG will be natural log-transformed before the imputation process, 
the data will be back transformed to create the imputed data set after the 
imputation. 
10.6.3.2 Analysis of Secondary Endpoints 
• The percent change in fasting TG from Baseline to Month 12 in the FAS will be 
analyzed in the same way as for the primary endpoint. 
• The proportion of patients who achieve fasting TG < 150 mg/dL (1.69 mmol/L) at 
Month 6 and proportion of patients who achieve fasting TG < 150 mg/dL at Month 12 
in the subset of FAS with Baseline TG < 500 mg/dL will be compared between each 
olezarsen treatment group and pooled placebo group using a logistic regression model 
with the treatment group as the factor, and log-transformed baseline TG as a 
covariate.  Missing TG values will be imputed using the same multiple imputation 
method as the primary analysis of the primary endpoint.  The analysis will be 
repeated in the subset of PPS with Baseline TG < 500 mg/dL as a sensitivity analysis.  
An additional sensitivity analysis will be conducted in the subset of FAS with 
Baseline TG < 500 mg/dL, in which all patients who have missing data due to 
discontinuation will be considered as non-responders. 
• The proportion of patients who achieve fasting TG < 500 mg/dL at Month 6 and 
proportion of patients who achieve fasting TG < 500 mg/dL at Month 12 will be 
analyzed in the same way as the proportion of patients who achieve fasting TG 
< 150 mg/dL.  It will be conducted in the subset of FAS or PPS with baseline TG 
≥ 500 mg/dL.   
• The percent change in fasting apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, 
HDL-C, TC, apoB, LDL-C, and apoA-1 from Baseline to Months 6 and 12 in the 
FAS will be analyzed in the same way as for the primary endpoint. 
• The adjudicated acute pancreatitis event rates in the subset of FAS with ≥ 2 events of 
adjudicated acute pancreatitis in 5 years prior to enrollment and in the FAS during the 
Treatment Period (Week 1 through Week 53/ET) will be compared between pooled 
olezarsen treatment and placebo group using a Negative Binomial regression model 
or Poisson regression model with the treatment group and log transformed baseline 
TG as the factors, and number of adjudicated acute pancreatitis events in 5 years prior 
to the enrollment as a covariate.  The logarithm of time in year that each patient 
observed during the Treatment Period will be used as an offset variable.  In the case 
of not enough events to perform the model-based analysis, the number and percentage 
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of subjects along with the two-sided 95% exact CI using Clopper-Pearson 
methodology will be summarized based on FAS. Fisher’s exact p-value will also be 
provided. 
Additional sensitivity analyses using different imputation models for continuous secondary 
efficacy endpoints will be conducted. The details will be provided in SAP. 
10.6.4 
Pharmacokinetic Analysis 
Pharmacokinetic (PK) analysis will include the following: 
• Determine trough (pre-dose) and post-treatment olezarsen plasma concentrations in 
all patients who receive Study Drug.  For all patients who receive olezarsen 
treatment, plasma concentrations over time will be summarized by treatment group, 
dose, day and time point, with and without stratification by ADA status, using 
descriptive statistics. 
• For patients who receive olezarsen treatment, the plasma disposition half-life 
associated with the apparent terminal elimination phase will be calculated using a 
non-compartment method, if appropriate, using available data.  Other PK parameters, 
as appropriate, may be determined or calculated at the discretion of the PK scientist.  
Plasma PK parameters will be summarized using descriptive statistics. 
Anti-drug antibody (ADA) analysis will include the following: 
• Evaluate immunogenicity (IM) (confirmed positive/negative and, when applicable, 
titer of anti-olezarsen antibodies) before, during, and after treatment with Study Drug 
(olezarsen or placebo) in all evaluable patients and appropriately summarize by 
treatment and dose over time. 
• Determine the IM incidence (number) and incidence rate (percent) at each evaluated 
study time point, and for the overall Treatment and Post-Treatment Evaluation Period 
and summarize by treatment and dose, as the total number of and percent of evaluated 
patients with antibody negative, positive, and unknown status. 
• Study patients with positive anti- olezarsen antibody status may be further classified 
(when applicable) as being either ‘persistent’, ‘transient’, or not determinable. 
• Determine patient level IM parameters, which will include but may not be limited to 
onset and peak titer. 
• Evaluate potential relationships of IM with selected efficacy, safety, and PK 
measures. 
Additional details regarding the PK and IM analysis will be described in the SAP. 
Population PK and covariate analysis may be performed if deemed appropriate, and results will 
be reported separately. 
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10.6.5 
Additional/Exploratory Analyses 
The proportion of patients who achieve various TG thresholds (e.g., fasting TG < 135 mg/dL, 
> 2000 mg/dL, etc.) and TG percent reductions (e.g., ≥ 40%, ≥ 50%, ≥ 60%, ≥ 70% reduction, 
etc.) at Months 6 and 12 will be compared between olezarsen and placebo groups. 
The adjudicated MACE incidence rates (number and percent of subjects) and event rates will be 
summarized by treatment group. 
Additional analyses of MACE composite of CV death, non-fatal MI, non-fatal ischemic stroke, 
and arterial revascularization (coronary and non-coronary), and the triple composite of CV death, 
non-fatal MI, and non-fatal ischemic stroke may be performed depending on rates of MACE. 
Details of the analyses will be provided 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 
patient population, based on an English version provided by the Sponsor or designee. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient 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 (olezarsen or placebo) are 
administered.   
Importantly, patients should be informed of the possibility and risks of a reduction in PLT count 
and other potential risks, in particular hepatic and renal risks, and the importance of strictly 
adhering to the monitoring program.  The patient or legally acceptable representative must be 
given sufficient time to consider whether to participate in the study.   
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient 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 patient or legally acceptable representative. 
If a potential patient 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 patient and must allow for questions.  Thereafter, both the patient or legally 
acceptable representative and the witness must sign the informed consent form to attest that 
informed consent was freely given and understood. 
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11.2 
Ethical Conduct of the Study 
The clinical trial is to be conducted in compliance with the protocol.  All applicable regulations 
and guidelines of current GCP, the Declaration of Helsinki as well as the demands of national 
drug and data protection laws and other applicable regulatory requirements must be followed.   
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  
A copy of the written approval of the protocol and informed consent form must be received by 
the Sponsor or designee before recruitment of patients 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 
IEC/IRB must also be received by the Sponsor or designee before recruitment of patients into the 
study and shipment of Study Drug.  The Investigator’s Brochure must be submitted to the 
IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with 
ICH GCP.  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 in accordance with local procedures.  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 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor or designee, patients should be identified by 
initials (if permitted by local law) and a patient 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 patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
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12 ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor 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 patients 
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 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.  Also, if new 
or emerging safety information affect the benefit/risk assessment of the clinical trial negatively, 
and with review and recommendation by the DSMB, the study would be terminated.  The 
Investigator/Sponsor or designee should notify the IEC/IRB in writing of the trial’s completion 
or early termination and send a copy of the notification to the Sponsor or designee. 
12.3 
Study Documentation and Storage 
An eCRF utilizing an Electronic Data Capture (EDC) application will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s 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.  In this study 
eCRF may not be used as source documents. 
The Investigator and Study Center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor or designee and/or applicable regulatory authorities.  Elements should include: 
• Patient 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 
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In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available for the duration required by GCP or local regulatory 
requirements, whichever is longer. 
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, in 
accordance with GCP. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
“visiting” (on-site or remote access) 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 patient confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research.  
The monitor should have access to patient medical records and other study-related records 
needed to verify the entries on the case report forms.  Source data should be attributable, legible, 
contemporaneous, original, and accurate (ALCOA) and must meet the regulatory requirements 
for recordkeeping. 
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.  
Sponsor will ensure the Investigators are trained about the importance of patient retention, 
compliance with study procedures, and requirements for recording reason for missed data in the 
case report form.  The Sponsor monitor or designee will ensure there is continuous oversight for 
compliance. 
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 
patient data received by the Sponsor or designee.  During this review, patient data will be 
checked for consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol and GCP.  To resolve any questions arising from the 
clinical data management review process, data queries and/or Study Center notifications will be 
sent to the Study Center for completion and return to Sponsor 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 in 
accordance with the general investigational plan. 
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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 patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any study-
related illness/injury in accordance with the information provided in the Compensation for Injury 
section of the Informed Consent document. 
 
 
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13 REFERENCES 
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APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J 2019; 40: 2785-
2796. 
Atzmon, G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserved pathway for 
exceptional longevity in humans. PLoS Biol 2006; 4: e113. 
Banks, PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis--2012: revision of 
the Atlanta classification and definitions by international consensus. Gut 2013; 62: 102-111. 
Bennett, CF. 2007. Chapter 10. Pharmacological Properties of 2'-O-Methoxyethyl-Modified 
Oligonucleotides. in S. T.  Crooke (ed.), Antisense Drug Technology: Principles, Strategies, and 
Applications (CRC Press: Boca Raton). 
Brahm, AJ, and Hegele RA. Chylomicronaemia--current diagnosis and future therapies. Nat Rev 
Endocrinol 2015; 11: 352-362. 
Breyer, ED, Le NA, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from 
VLDL: effect of particle size. J Lipid Res 1999; 40: 1875-1882. 
Brown, RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic 
lipase and endothelial lipase on the metabolism of both high-density lipoproteins and 
apolipoprotein B-containing lipoproteins. Circ Res 2010; 107: 357-364. 
Brown, WV, Brunzell JD, Eckel RH, et al. Severe hypertriglyceridemia. J Clin Lipidol 2012; 6: 
397-408. 
Brown, WV, Gaudet D, Goldberg I, et al. Roundtable on etiology of familial chylomicronemia 
syndrome. J Clin Lipidol 2018; 12: 5-11. 
Carpenter, JR, Roger JH, and Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat 2013; 23: 1352-1371. 
Chait, A, and Brunzell JD. Chylomicronemia syndrome. Adv Intern Med 1992; 37: 249-273. 
Dron, JS, Wang J, McIntyre AD, et al. The polygenic nature of mild-to-moderate 
hypertriglyceridemia. J Clin Lipidol 2020; 14: 28-34 e22. 
Gaudet, D, Alexander VJ, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in 
Patients with Hypertriglyceridemia. N Engl J Med 2015; 373: 438-447. 
Gaudet, D, Blom DJ, Bruckert E, et al. Familial ChylomicronemiaSyndrome (FCS) Patients 
Recruited to the APPROACH Trial of VolanesorsenTherapy are Representative of Subjects with 
FCS. In,2016.  
Gaudet, D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia 
syndrome. N Engl J Med 2014; 371: 2200-2206. 
Gordts, PL, Nock R, Son NH, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins 
through LDL family receptors. J Clin Invest 2016; 126: 2855-2866. 
Graham, MJ, Lee RG, Bell TA, 3rd, et al. Antisense oligonucleotide inhibition of apolipoprotein 
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Grundy, SM, Stone NJ, Bailey AL, et al. 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on 
the Management of Blood Cholesterol: A Report of the American College of 
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Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 
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Hicks, KA, Mahaffey KW, Mehran R, et al. 2017 Cardiovascular and Stroke Endpoint 
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Iqbal, Z, Ho JH, Adam S, et al. Managing hyperlipidaemia in patients with COVID-19 and 
during its pandemic: An expert panel position statement from HEART UK. Atherosclerosis 
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Ito, Y, Azrolan N, O'Connell A, et al. Hypertriglyceridemia as a result of human apo CIII gene 
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Kaatz, S, Ahmad D, Spyropoulos AC, et al. Definition of clinically relevant non-major bleeding 
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2126. 
Kinnunen, PK, and Ehnolm C. Effect of serum and C-apoproteins from very low density 
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Langsted, A, Madsen CM, and Nordestgaard BG. Contribution of remnant cholesterol to 
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Lemieux, I, Salomon H, and Despres JP. Contribution of apo CIII reduction to the greater effect 
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Levey, AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
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Mach, F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of 
dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41: 111-188. 
Mendivil, CO, Zheng C, Furtado J, et al. Metabolism of very-low-density lipoprotein and low-
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NCEP, K, M. B. Update on managing hypercholesterolemia. The new NCEP guidelines. Aaohn j 
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Neunert, C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for 
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Norata, GD, Tsimikas S, Pirillo A, et al. Apolipoprotein C-III: From Pathophysiology to 
Pharmacology. Trends Pharmacol Sci 2015; 36: 675-687. 
Nordestgaard, BG, and Varbo A. Triglycerides and cardiovascular disease. Lancet 2014; 384: 
626-635. 
Petersen, KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty 
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Pollin, TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable 
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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. 
Provan, D, Arnold DM, Bussel JB, et al. Updated international consensus report on the 
investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3: 3780-
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Provan, D, Stasi R, Newland AC, et al. International consensus report on the investigation and 
management of primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Schafer, JL. Analysis of Incomplete Multivariate Data.  eBook 
http://www.ii.uni.wroc.pl/~bitro/wojtki/e_book/Analisis/4061fm.pdf. Chapman and Hall/CRC 
1997. 
Schafer, JL. Multiple imputation: a primer. Stat Methods Med Res 1999; 8: 3-15. 
Schulman, S, and Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694. 
Schwartz, GG, Abt M, Bao W, et al. Fasting triglycerides predict recurrent ischemic events in 
patients with acute coronary syndrome treated with statins. J Am Coll Cardiol 2015; 65: 2267-
2275. 
Symersky, T, van Hoorn B, and Masclee AA. The outcome of a long-term follow-up of 
pancreatic function after recovery from acute pancreatitis. Jop 2006; 7: 447-453. 
Tardif, JC, Karwatowska-Prokopczuk E, Amour ES, et al. Apolipoprotein C-III reduction in 
subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J 2022; 
43: 1401-1412. 
Taskinen, MR, Packard CJ, and Boren J. Emerging Evidence that ApoC-III Inhibitors Provide 
Novel Options to Reduce the Residual CVD. Curr Atheroscler Rep 2019; 21: 27. 
Thygesen, K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction 
(2018). J Am Coll Cardiol 2018; 72: 2231-2264. 
Virani, SS, Morris PB, Agarwala A, et al. 2021 ACC Expert Consensus Decision Pathway on the 
Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia: A 
Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll 
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Zhang, H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway factor 
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Blood 2010; 116: 4684-4692. 
 
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14 APPENDICES 
 
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APPENDIX A. SCHEDULE OF PROCEDURES 
 
ScreeningA 
Treatment Period 
Follow up Period 
Run-in QualM 
Study Week 
-4 
to -2 
-2 
to -1 
1 
5M 
9M 
13M 17M 21M 25/ET-
L1M,N 
27/ET-
L2M,N 
29M 33M 37M 41M 45M 49M 
51/ET-
L3M,N 
53/ET-
L4M,N or 
Tx ETM 
4M,O 8M,O 
13M,O or 
Post-Tx 
ETM 
Study Day 
-28 to 
-15 
-14 
to -1 
1B 
29 
57 
85 113 141 
169 
183 
197 225 253 281 309 337 
351 
365 
28 
56 
91 
Visit and Testing Window ± Days 
-28 
0 
-3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHC, TSH, free T4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and HeightD 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Physical Examination 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
12-lead ECG 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Pregnancy TestE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Extended UrinalysisF 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
ChemistryG,H 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
HematologyH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Coagulation (aPTT, PT, INR) 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Lipid PanelG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
HbA1c  
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
hsCRP 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-drug Antibody (ADA) I 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Plasma PK - olezarsen I 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Archived Serum & Plasma SamplesH,J 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet/Life-style/Alcohol CounselingK 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Study Drug:  SC InjectionL 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
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All procedures and study sample collections are to be done pre-dose at respective visits, unless specified otherwise 
Legend 
A Eligible patients will enter an approximately 4-week Screening Period (that may be extended to 8 weeks if assessments can’t be completed 
within the 4-week period) that includes an at least 2-week Diet/life-style Stabilization/Run-In Period and an approximately 2-week Qualification 
Period 
B Day 1/Baseline assessments can be performed up to 3 days (-3 days) prior to the actual Day 1 visit, which is the day of first Study Drug dose 
C For confirmation of menopause at Screening per inclusion criteria 
D Height only required at Screening 
E Women who are not surgically sterile or post-menopausal.  A serum pregnancy test will be performed during run-in and urine pregnancy tests 
will be performed at all other study visits  
F All tests listed in Appendix B under Extended Urinalysis should be performed, including routine urinalysis, urine microscopy, UACR, and 
UPCR.  Urine collection for urinalysis should not be performed during menstruation. 
G Blood samples to be collected after an overnight fast of at least 10 hours.  Fasting is not required for confirmatory tests, repeated uninterpretable, 
or missing tests, or tests taken for safety reasons 
H If the PLT, renal function, 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 3 days and not later than 7 days).  All PLT count, liver chemistry, or renal 
function results will be reviewed promptly (within 2 business days of receipt) by the Investigator.  Any case of a PLT count < 50,000/mm3 
should be reported in an expedited fashion to the Sponsor 
I PK/ADA samples will be collected prior to dose administration (pre-dose) during Weeks 1-49 of the Treatment Period, and any time at the end 
of the Treatment Period (Week 53) and during follow up or ET visit, as specified in Appendix C 
J Serum and plasma archive samples will be collected and stored for follow-up exploration of laboratory findings, cardiometabolic disease 
relationship, and/or AEs (e.g., measurement of cytokine and/or chemokine levels, measurement of additional markers of kidney function, 
measurement of antibodies, etc.) in this or subsequent clinical studies of olezarsen.  Samples may be stored up to 20 years 
K Recommended time points for qualified site personnel to reinforce compliance to diet/ life-style modifications and alcohol restrictions 
(Appendix E) 
L Study Drug can be administered at home by patient or caregiver after receiving appropriate training 
M Assessments and procedures to be conducted by either the Study Center or by a Home Healthcare service (if available and permitted by local 
regulations) as arranged by the Study Center personnel.  Physical Exam will be Body Assessment if conducted by a Home Healthcare 
professional 
N  Landmark visit.  For early termination landmark (ET-L) visits:  Week 25 is ET-L1, Week 27 is ET-L2, Week 51 is ET-L3, and Week 53 is ET-
L4 
O Weeks/days from end of treatment.  End of treatment is defined as 1 dosing interval (4 weeks) post-last dose 
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APPENDIX B.  LIST OF LABORATORY ANALYTES 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of olezarsen or other similar 
oligonucleotides. 
Clinical Chemistry 
Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Uric Acid 
• Total bilirubin 
• Direct (conjugated) 
bilirubin 
• Indirect 
(unconjugated) 
bilirubin 
• ALT 
• AST 
• ALP 
• Creatine kinase 
• GGT 
 
Screening Tests 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• HIV antibody 
• FSH (for confirmation 
of menopause at 
screening per 
inclusion criteria) 
• Serum βhCG (only 
women who are not 
surgically sterile or 
post-menopausal) 
• TSH, free T4 
 
Coagulation 
• aPTT 
• PT 
• INR 
 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
(ultracentrifugation) 
• HDL cholesterol 
• ApoB 
• Triglycerides 
• VLDL cholesterol 
• ApoC-III 
• Non-HDL-C 
• ApoA-1 
• Remnant cholesterol  
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, 
MCHC, RDW 
• Platelets 
• MPV 
• White blood cells 
(WBC)  
• WBC Differential  
(% and absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Pharmacokinetics1 
• Olezarsen (total full 
length ASO) 
concentration in 
plasma 
 
Immunogenicity 
• Anti- olezarsen 
antibodies (ADA) 
 
Other assessments 
• HbA1c 
Extended Urinalysis 
• Routine Urinalysis 
- Color 
- Appearance 
- Specific gravity 
- pH 
- Protein 
- Blood 
- Glucose 
- Ketones 
- Bilirubin 
- Urobilinogen 
- Leukocyte esterase 
- Nitrate 
• Microscopic 
examination 
• P/C Ratio (UPCR) 
• A/C Ratio (UACR) 
 
Inflammation 
• hsCRP 
1Plasma and immunogenicity samples may also be used for profiling of drug binding proteins, bioanalytical 
method validation purposes, stability assessments, metabolite assessments, IM testing (or possibly for purposes 
of IM assay development and/or validation), or to assess other actions of olezarsen with plasma constituents. 
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APPENDIX C. PK AND ADA SAMPLING SCHEDULE  
Blood samples for the determination of plasma olezarsen concentrations and ADA assessment will be collected prior to dosing, and at 
various time points throughout the Post-Treatment Follow-up Period as noted in the table below.  Plasma PK and ADA samples may 
also be used for profiling of drug binding proteins, bioanalytical method validation purposes, stability and metabolite assessments, 
IM testing (or possibly for purposes of IM assay development and/or validation), or to assess other actions of olezarsen with plasma 
constituents. 
Plasma Trough and Post-Treatment Sampling Schedule for all Patients 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
5 
13 
25/ET-
L1** 
37 
53/ET-L4** or 
Tx ET 
4* 
8* 
13/ Post-Tx 
ET* 
Study 
Day 
1 
29 
85 
169 
253 
365 
28* 
56* 
91* 
 
Pre-dose  
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Any time 
PK only  
Any time 
PK only  
Any time 
Any time 
*Weeks/days from end of treatment.  End of treatment is defined as 1 dosing interval (4 weeks) post-last dose 
**Landmark visit.  For early termination (ET-L) visits:  Week 25 is ET-L1 and Week 53 is ET-L4 
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APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING 
TO LABORATORY ABNORMALITIES 
The following grading recommendations for AEs relating to lab test abnormalities are based 
upon the (CTCAE) Version 5.0, November 2017 with modifications outlined in the footnotes 
below. 
 
 
 
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Amendment 2 
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The following grading recommendations for AEs at the injection site are based upon the Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, Sept 2007 
 
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Amendment 2 
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APPENDIX E. GUIDELINES FOR MANAGEMENT OF 
HYPERTRIGLYCERIDEMIA (LIFE-STYLE 
INTERVENTIONS AND STANDARD OF CARE LIPID 
LOWERING THERAPY)  
Management of hypertriglyceridemia should consist of life-style interventions (including 
optimization of diet, weight loss, intensification of physical activity) and use of lipid-lowering 
medications as described in the 2019 ESC/EAS Guidelines for the Management of 
Dyslipidaemias (Mach et al. 2020) and the most recent 2021 ACC Expert Consensus Decision 
Pathway on the management of ASCVD risk reduction in patients with persistent 
hypertriglyceridemia (Virani et al. 2021).  
The guidance for the clinical workflow of patients with clinical ASCVD and fasting TGs 
≥ 150 mg/dL and < 500 mg/dL (Virani et al. 2021) is shown in the figure below. 
 
 
 
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Amendment 2 
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82 
The recommended lipid lowering therapies for patients with SHTG are provided below. 
1. If baseline TG levels are 500-879 mg/dL: 
• Consider fibrate or prescription strength omega-3 fatty acids (icosapent ethyl or 
omega-3 carboxylic acids) 
• Statin therapy encouraged.  If the patient has established ASCVD, diabetes, or is high 
risk (e.g., > 7.5% 10-yr risk of ASCVD per the Pooled Cohort Equation, or 
≥ 5% 10-year risk or fatal CV disease per SCORE), then the patient should be on 
statin therapy unless intolerant, in which case ezetimibe is strongly suggested 
2. If baseline TG levels are ≥ 880 mg/dL: 
• Should be on fibrate and/or prescription strength omega-3 fatty acids unless neither is 
tolerated 
• Should be on statin therapy. Must be on some form of lipid-lowering therapy, ideally 
statin + TG lowering drug 
 
 
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Dietary Recommendations for patients with hypertriglyceridemia are provided in the table below 
(Virani et al. 2021). 
 
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APPENDIX F. CLINICAL DIAGNOSIS OF ASCVD AND METABOLIC 
SYNDROME 
Clinical Diagnosis of ASCVD: 
1. Documented CAD (at least 1 of the following criteria must be satisfied): 
• Angiographic evidence of ≥ 50% stenosis in 1 or more major epicardial coronary 
arteries 
• Documented prior myocardial infarction 
• History of coronary revascularization (PCI or CABG) 
• Evidence of cardiac ischemia on exercise stress test/imaging 
• Coronary artery calcium (CAC) score > 100 
2. Documented cerebrovascular disease (at least 1 of the following criteria must be 
satisfied): 
• Documented prior ischemic stroke 
• Carotid artery disease with ≥ 50% carotid artery stenosis 
• History of carotid artery revascularization 
3. Documented peripheral artery disease (at least 1 of the following criteria must be 
satisfied): 
• Ankle-brachial index (ABI) < 0.9 with symptoms of intermittent claudication 
• History of aorto-iliac or peripheral arterial intervention 
• Amputation involving the lower extremity due to peripheral artery disease  
Clinical Diagnosis of Metabolic Syndrome: 
Metabolic syndrome is defined by at least 3 of the 5 below (Grundy et al. 2019):  
• Elevated waist circumferences, defined as ≥ 102 cm (40.1 inches) (or 90 cm 
[35.4 inches]) in males and ≥ 88 cm (34.6 inches) (or 80 cm [31.4 inches]) in 
females*  
• Elevated triglycerides ≥ 175 mg/dL (2.0 mmol/L†) or treatment for elevated 
triglycerides  
• Reduced HDL-C < 40 mg/dL (< 1.0 mmol/L) in men, < 50 mg/dl (< 1.3 mmol/L) in 
women, or drug treatment for low HDL-C  
• Hypertension defined a systolic blood pressure ≥ 130 mmHg and/or diastolic blood 
pressure ≥ 85 mmHg or antihypertensive drug treatment in a patient with a history of 
hypertension  
• Elevated fasting glucose ≥ 100 mg/dL or hemoglobin A1c above the upper limit of 
normal, or drug treatment of elevated glucose  
* Waist circumference cut points generally recommended for the United States are ≥ 102 cm in males and ≥ 88 cm 
in females, but lower cut points (≥ 90 cm in males and ≥ 80 cm in females) are commonly recommended for other 
populations.  
† Categorical cut point for triglycerides incorporates both fasting and non-fasting triglycerides.  
Page 85 of 86

Version: 1
Version Date: 24 Mar 2023
Title: 678354-CS8 Protocol - Amend 2: A Randomized, Double-blind, Placebo-Controlled,
Ph 2b Study of ISIS 678354 in Patients with Hypertriglyceridemia and
Atherosclerotic CD (Established or at Increased Risk for), and/or with Severe
, 24-Mar-2023 21:35:36 GMT+0000
APPROVALS:
Protocol
Page 86 of 86
PPD
PPD

Clinical Study Report  
CONFIDENTIAL 
Ionis Pharmaceuticals, Inc.
Study Number:  ISIS 678354-CS8 
Version 1
16. Appendices 
 
1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan, Version 1.0 (17 October 2023), is provided. 
Page 1 of 54

 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Phase 2b 
Study of Olezarsen (ISIS 678354) in Patients with 
Hypertriglyceridemia and Atherosclerotic Cardiovascular 
Disease (Established or at Increased Risk for), and/or with 
Severe Hypertriglyceridemia 
 
 
Protocol Number: 
ISIS 678354-CS8 
 
 
Protocol Version/Date: 
Protocol Amendment 2/March 22, 2023 
 
 
Investigational Product: Olezarsen 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
 
 
SAP Version/Date: 
Version 1.0/October 17, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
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Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
ISIS 678354-CS8 
 
Version 1.0/October 17, 2023 
 
Page 4 of 52 
VERSION HISTORY  
 
Version 
Version Date 
Description 
1.0 
October 17, 2023 
Original signed version 
 
 
 
 
 
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Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
ISIS 678354-CS8 
 
Version 1.0/October 17, 2023 
 
Page 5 of 52 
TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 9 
2 
Study Objectives ................................................................................................................. 9 
2.1 
Primary Objective......................................................................................................... 9 
2.2 
Secondary Objectives .................................................................................................. 9 
2.3 
Exploratory Objectives ................................................................................................. 9 
2.4 
Safety and Tolerability Objective .................................................................................. 9 
2.5 
PK Objective ................................................................................................................ 9 
3 
INVESTIGATIONAL PLAN .................................................................................................10 
3.1 
Overall Study Design and Plan ...................................................................................10 
3.2 
Study Endpoints ..........................................................................................................10 
3.2.1 
Primary Endpoint .................................................................................................10 
3.2.2 
Secondary Endpoints ...........................................................................................10 
3.2.3 
Exploratory Endpoints ..........................................................................................11 
3.2.4 
Safety and Tolerability Endpoints .........................................................................11 
3.2.5 
PK Endpoints .......................................................................................................11 
4 
Statistical Methodology ......................................................................................................11 
4.1 
Data Management and Quality Assurance ..................................................................11 
4.1.1 
Central Laboratory Data .......................................................................................11 
4.1.2 
Pharmacokinetic Data ..........................................................................................11 
4.1.3 
Adjudicated Data .................................................................................................12 
4.2 
General Considerations ..............................................................................................12 
4.2.1 
Data Presentation ................................................................................................12 
4.2.2 
Definition of Baseline, Month 6 and Month 12 ......................................................13 
4.2.3 
Analysis Visit Windows ........................................................................................14 
4.3 
Software .....................................................................................................................15 
4.4 
Study Subjects ............................................................................................................15 
4.4.1 
Disposition of Subjects .........................................................................................15 
4.4.2 
Protocol Deviations ..............................................................................................16 
4.5 
Demographic and Baseline Characteristics .................................................................16 
4.6 
Analysis Sets ..............................................................................................................16 
4.7 
Medical History ...........................................................................................................17 
4.8 
Prior and Concomitant Medication ..............................................................................19 
4.9 
Efficacy Evaluation......................................................................................................19 
4.9.1 
Analysis and Data Conventions ...........................................................................20 
4.9.2 
Primary Efficacy Variable .....................................................................................27 
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Statistical Analysis Plan 
ISIS 678354-CS8 
 
Version 1.0/October 17, 2023 
 
Page 6 of 52 
4.9.3 
Secondary Efficacy Variables ..............................................................................30 
4.10 
Safety Evaluation ........................................................................................................33 
4.10.1 
Extent of Exposure and Treatment Compliance ...................................................33 
4.10.2 
Adverse Events ....................................................................................................34 
4.10.3 
Clinical Laboratory Evaluation ..............................................................................40 
4.10.4 
Vital Signs and Physical Findings ........................................................................45 
4.10.5 
12-Lead Electrocardiograms (ECGs) ...................................................................45 
4.10.6 
Data and Safety Monitoring Board (DSMB) ..........................................................46 
4.11 
Other Analyses ...........................................................................................................46 
4.11.1 
Pharmacokinetics ................................................................................................46 
4.11.2 
Immunogenicity (IM) Analysis ..............................................................................47 
4.11.3 
Additional/Exploratory Analyses ...........................................................................50 
4.12 
Determination of Sample Size .....................................................................................50 
4.13 
Changes to Protocol-planned Analyses ......................................................................50 
5 
REFERENCES ..................................................................................................................51 
6 
APPENDICES ....................................................................................................................52 
6.1 
Appendix A – Grading Scale for Selected Lab Analytes with Abnormal Values ...........52 
 
TABLE OF TABLES  
Table 1: 
Analysis Windows (Days) ........................................................................................15 
 
 
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Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
ISIS 678354-CS8 
 
Version 1.0/October 17, 2023 
 
Page 7 of 52 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADA 
anti-drug antibodies 
AE 
Adverse event 
AESI 
adverse event of special interest 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance  
aPTT 
activated partial thromboplastin time 
apoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
ASCVD 
atherosclerotic CV disease 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
BMI 
body mass index 
BUN 
blood urea nitrogen 
CAD 
coronary artery disease 
CIR 
copy increment from reference 
CIs 
confidence intervals 
CK 
creatinine kinase 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBL 
database lock 
DBP 
diastolic blood pressure 
DSMB 
Data and Safety Monitoring Board 
ECGs 
electrocardiograms 
eCRF 
electronic Case Report Form 
eDISH 
evaluation of Drug Induced Serious Hepatoxicity 
ET 
early termination  
FMQ 
FDA Medical Query 
FLRs 
flu-like reactions 
GGT 
gamma-glutamyl transferase 
HbA1c 
hemoglobin a1c 
HDL-C 
high-density lipoprotein cholesterol 
hsCRP 
CRP measured by high sensitivity assay 
ICEs 
intercurrent events  
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IM 
immunogenicity 
ISIS 678354 
antisense inhibitor of apoC-III, olezarsen 
ISR 
Injection site reaction  
ITT 
intent-to-treat 
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Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
ISIS 678354-CS8 
 
Version 1.0/October 17, 2023 
 
Page 8 of 52 
Abbreviation 
Definition 
LCRIS 
local cutaneous reaction at injection site  
LDL-C 
low-density lipoprotein cholesterol 
LFT 
Liver Function Test 
LS 
least squares 
MACE 
major adverse cardiovascular event 
MACE-AC 
MACE-Adjudication Committee  
MAR 
missing at random 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCMC 
Markov Chain Monte Carlo 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MNAR 
missing not at random  
MPV 
mean platelet volume 
Non-HDL-C 
non-high density lipoprotein cholesterol 
PAC 
Pancreatitis Adjudication Charter 
PCI 
percutaneous coronary intervention 
PK 
pharmacokinetic 
PMM 
pattern mixture models  
PPS 
per protocol set 
PLT 
platelet 
PT 
preferred term 
QTcF 
QTc interval calculated using Fridericia’s formula 
Q4W 
every 4 weeks 
RDW 
red cell distribution width 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SEM 
standard error of mean 
SHTG 
severe hypertriglyceridemia 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TC 
total cholesterol 
TG 
triglycerides 
UACR 
urine albumin/creatinine ratio 
ULN 
upper limit of normal  
UPCR 
urine protein/creatinine ratio  
VLDL-C 
very low-density lipoprotein cholesterol 
VR 
ventricular rate 
WBC 
white blood cell 
WHO-DDE 
World Health Organization - Drug Dictionary Enhanced 
 
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Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
ISIS 678354-CS8 
 
Version 1.0/October 17, 2023 
 
Page 9 of 52 
1 INTRODUCTION  
This Statistical Analysis Plan (SAP) describes the methodologies, rules, and conventions to be 
used in the presentation and analysis of the efficacy, safety, and pharmacokinetics (PK) for 
Protocol ISIS 678354-CS8.  
The analyses described in this SAP are based upon the following study documents: 
• 
Study Protocol (Amendment 2: Mar 22, 2023) 
• 
electronic Case Report Form (eCRF) (Sep 26, 2023) 
Revision(s) of this SAP will not be required for any subsequent amendments to the protocol which 
do not change the analyses described in this SAP. The SAP will be finalized prior to database 
lock (DBL). If circumstances should arise during the study rendering this analysis inappropriate, 
or if improved methods of analysis should arise, updates to the analyses may be made. Any 
deviations from the SAP after DBL, reasons for such deviations and all alternative or additional 
statistical analyses that may be performed, will be documented in the final clinical study report. 
2 STUDY OBJECTIVES  
2.1 
Primary Objective  
To evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels 
compared to placebo. 
2.2 
Secondary Objectives  
To evaluate the effect of olezarsen as compared to placebo on: 
• 
Percent change in fasting TG levels upon longer duration of treatment (1 year) 
• 
Proportion of patients who achieve different thresholds in fasting TG levels 
• 
Percent change in fasting apolipoprotein C-III (apoC-III), very low-density lipoprotein 
cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol 
(non-HDL-C), high- density lipoprotein cholesterol (HDL-C), total cholesterol (TC), 
apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein 
A-1 (apoA-1) 
• 
Adjudicated acute pancreatitis event rate in patients with ≥ 2 events of adjudicated acute 
pancreatitis in 5 years prior to enrollment 
• 
Adjudicated acute pancreatitis event rate 
2.3 
Exploratory Objectives  
To evaluate the effect of olezarsen on the incidence of major adverse cardiovascular events 
(MACE) 
2.4 
Safety and Tolerability Objective  
To evaluate safety and tolerability of olezarsen 
2.5 
PK Objective  
To evaluate PK of olezarsen 
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Statistical Analysis Plan 
ISIS 678354-CS8 
 
Version 1.0/October 17, 2023 
 
Page 10 of 52 
3 INVESTIGATIONAL PLAN  
3.1 
Overall Study Design and Plan  
The 678354-CS8 study is a multi-center, randomized, double-blind, placebo-controlled trial done 
in conjunction with the TIMI Study Group, an academic research organization based at Brigham 
and Women’s Hospital and Harvard Medical School. Eligible patients will enter an approximately 
4-week Screening Period (that may be extended to 8 weeks if assessments can’t be completed 
within the 4-week period) that includes an at least 2-week Diet/ life-style Stabilization/Run-in 
Period, and an approximately 2-week Qualification Period. Following Qualification, approximately 
152 eligible patients will be randomized 1:1 to Cohort A (50 mg) or Cohort B (80 mg) and each 
cohort further randomized 3:1 to receive olezarsen or placebo in a 53-week Treatment Period. 
Patients in Cohort A will receive 50 mg of olezarsen once every 4 weeks (Q4W) or matching 
volume of placebo (0.5 mL) during Weeks 1-49 of the Treatment Period. Patients in Cohort B will 
receive 80 mg olezarsen once Q4W or matching volume of placebo (0.8 mL) during Weeks 1-49 
of the Treatment Period. The 80 mg once Q4W may be adjusted to 50 mg once Q4W due to 
tolerability or safety reasons at any point during the study following consultation with the Sponsor 
Medical Monitor or designee. Randomization will be stratified by Qualification fasting TG levels of 
< 500 mg/dL vs ≥ 500 mg/dL. Following the Week 53 visit, patients will enter the 13-week 
Post-Treatment Follow-up Period. All endpoints will be evaluated after the last patient has 
completed the Week 53/early termination (ET) Visit. 
3.2 
Study Endpoints  
3.2.1 
Primary Endpoint  
Percent change in fasting TG from Baseline at Month 6 (average of Weeks 25 and 27) 
compared to placebo. 
3.2.2 
Secondary Endpoints  
• 
Percent change in fasting TG from Baseline at Month 12 (average of Week 51 and 
Week 53) compared to placebo.  
• 
Proportion of patients who achieve fasting TG < 150 mg/dL (1. 69 mmol/L) at Month 6 
and proportion of patients who achieve fasting TG < 150 mg/dL at Month 12 compared 
to placebo in the subgroup of patients with baseline fasting TG < 500 mg/dL (5.65 
mmol/L).  
• 
Proportion of patients who achieve fasting TG < 500 mg/dL (5.65 mmol/L) at Month 6 
and proportion of patients who achieve fasting TG < 500 mg/dL at Month 12 compared 
to placebo in the subgroup of patients with baseline fasting TG ≥ 500 mg/dL.  
• 
Percent change in fasting apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, HDL-C, 
TC, apoB, LDL-C, and apoA-1 from Baseline at Month 6 and at Month 12 compared to 
placebo. 
• 
Adjudicated acute pancreatitis event rate during the Treatment Period compared to 
placebo in patients with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment 
• 
Adjudicated acute pancreatitis event rate during the Treatment Period compared to 
placebo 
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Statistical Analysis Plan 
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Version 1.0/October 17, 2023 
 
Page 11 of 52 
3.2.3 
Exploratory Endpoints  
• 
Events rates of independently adjudicated MACE.  
• 
Additional analyses of the broader MACE composite of CV death, non-fatal MI, non-fatal 
ischemic stroke, or arterial revascularization (coronary or non-coronary) 
• 
The triple composite of CV death, non-fatal MI, and non-fatal ischemic stroke and its 
individual components (CV death; MI; ischemic stroke) may be performed depending on 
rates of MACE. 
3.2.4 
Safety and Tolerability Endpoints  
Safety and tolerability assessments include adverse events (AEs), vital signs and weight, 
physical examinations, clinical laboratory tests, electrocardiogram (ECG), and use of 
concomitant medications. Safety and tolerability results in patients receiving olezarsen will be 
compared with those receiving placebo. 
3.2.5 
PK Endpoints  
Plasma trough and post-treatment concentrations of olezarsen, and potential exposure/ 
response relationship for apoC-III and TG. 
4 STATISTICAL METHODOLOGY  
4.1 
Data Management and Quality Assurance  
4.1.1 
Central Laboratory Data  
Ionis Pharmaceuticals, Inc. (Ionis) and Medpace are responsible for the format of the laboratory 
electronic data transfers and the transfer schedule. Central laboratory data results are not stored 
in the EDC system. Medpace and Ionis are responsible for the review of the clinical laboratory 
data. This process involves reviewing the patient and visit identifiers in the central laboratory data 
results against the central lab data identifiers collected in the EDC system. Investigator sites have 
access to the data via lab reports sent directly from the laboratory or through the laboratory’s web 
portal (in which case Investigators only have access to data from their site). 
The patients, Investigators, study staff, and the Sponsor are to remain blinded to central and local 
lipid data (TG, apoC-III, TC, HDL-C, remnant cholesterol, apoB, VLDL-C, non-HDL-C, LDL-C, 
and apoA-1) starting after the first dose on Day 1 then throughout the remainder of the study or 
as noted for TG or apoB alerts per Section 8.5.7 of the study protocol. 
4.1.2 
Pharmacokinetic Data  
Ionis is responsible for the management and review of the PK data. This process involves 
reviewing the patient and visit identifiers with the clinical data collected in the EDC system. The 
PK data are not stored in the EDC system. Prior to unblinding of the final analysis, any PK 
concentration datasets provided to Ionis by the bioanalytical lab will be provided without reference 
to actual patient identifiers to avoid inadvertent or accidental unblinding. The bioanalytical lab may 
provide Ionis with datasets containing dummy patient identifiers unrelated to the actual identifiers 
to allow review of the PK data. 
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4.1.3 
Adjudicated Data  
All AEs and serious AEs (SAEs) that occur during the study that are consistent with an event of 
acute pancreatitis will be adjudicated by a blinded, independent committee according to the 
Atlanta classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Acute 
Pancreatitis Adjudication Charter (PAC). In addition, data for episodes of acute pancreatitis or 
suspected pancreatitis in the 5 years prior to enrollment will be collected by review of each 
patient’s medical chart and these events will also be adjudicated. 
All AEs and SAEs that occur during the study that are consistent with a MACE will be adjudicated 
by a blinded, independent MACE-Adjudication Committee (MACE-AC) as outlined in the MACE 
Adjudication Charter. 
The MACE-AC will adjudicate all fatal events and events suggestive of non-fatal myocardial 
infarction, hospitalization for unstable angina, hospitalization for (worsening) heart failure, 
coronary or non-coronary revascularization procedures, or stroke. The criteria used by the 
MACE-AC to determine the occurrence of any of the events will follow the recommendations 
included in published Cardiovascular and Stroke Endpoint Definitions for Clinical Trials (Hicks et 
al. 2018; Thygesen et al. 2018). 
4.2 
General Considerations  
4.2.1 
Data Presentation  
Descriptive summary statistics including the number of subjects with non-missing data (n), mean, 
median, standard deviation (SD), standard error of mean (SEM), 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. The minimum 
and maximum will be reported to the same number of decimal places as the raw data recorded in 
the database. The mean, median, lower quartile and upper quartile will be reported to one more 
decimal place than the raw data recorded in the database. The SD and SEM will be reported to 
two more decimal places than the raw data recorded in the database. In general, the maximum 
number of decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of n, frequency counts and percentages. 
Percentages will be rounded to one decimal place unless it is an integer.  Percentages will not be 
presented for zero counts.  
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
All statistical tests will be conducted using 2-sided tests with 5% Type 1 error rates unless 
otherwise stated. Where appropriate, p-values will be reported. P-values greater than or equal to 
0.0001, in general, will be presented to four decimal places. P-values less than 0.0001 will be 
presented as “< 0.0001”. 
Confidence intervals (CIs) will be presented to one more decimal place than the raw data. 
The primary endpoint will be assessed on the Full Analysis Set (FAS) and Per Protocol Set (PPS), 
with the former being the basis for the primary efficacy analysis. All the secondary endpoints will 
be assessed on the FAS. All safety assessments will be performed on the Safety Set. PK 
endpoints will be assessed in the PK Set as applicable. 
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Efficacy and safety results will be summarized under the treatment to which patients are 
randomized. For safety results, should there be any cases after unblinding in which a patient 
received treatment other than what was randomized, such cases will be discussed and noted in 
footnotes where applicable. 
The efficacy summaries will be presented by the treatment group (placebo, olezarsen 50 mg, 
olezarsen 80 mg). The disposition, demographics, baseline characteristics, medical history, prior 
and concomitant medications, and protocol deviations will be presented by treatment group, total 
olezarsen treated (50 mg + 80 mg) and overall. The safety data will be presented by the treatment 
group and total olezarsen treated. 
All tables and figures containing efficacy endpoints will indicate whether they present raw data or 
adjusted results from the statistical model, with footnotes indicating the model used and 
covariates included in the model.  
Selected safety endpoints will be analyzed using below analysis method: 
• 
The crude incidence rates, risk difference with 95% CI between each active treatment 
group (or total olezarsen treated) and pooled placebo group. The crude incidence rate 
(in percentage) is defined as the number of patients who experienced at least one event 
times 100 divided by the total number of patients. The 95% CI of risk difference in crude 
incidence rate will be estimated using the unstratified Miettinen-Nurminen (MN) method.  
• 
Exposure- adjusted incidence rate (EAIR) rates, EAIR difference with 95% CI between 
each active treatment group (or total olezarsen treated) and pooled placebo group. EAIR 
is defined as the number of patients who experienced at least one event times 100 
divided by total person-years at risk for the event. For patients with events, the time at 
risk is the time from the first dose date to the first onset of an event (i.e., first event date 
minus first dose date plus one day divided by 365.25); for patients with no event, the 
time at risk is the total duration in the on-study period in year (i.e., last participation date 
or data cutoff date minus first dose date plus one day divided by 365.25). The difference 
of EAIR and 95% CI will be estimated using Wald’s method. 
• 
Exposure-adjusted event rate (EAER), defined as the number of events times 
100 divided by the total duration in the on-study period in year. 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Medpace (a CRO that is responsible for 
pre-programming datasets and TLFs for the Study) procedures.  
Missing visits or missing data related to COVID-19 may be listed. Additional listings may be 
provided for all patients impacted by COVID-19 during conduct of the study. Additional summary 
(s) and/or analyses may be provided if deemed necessary. 
4.2.2 
Definition of Baseline, Month 6 and Month 12  
Baseline lipid measurements are defined as the average of the pre-dose measurement on Day 1 
and all measurements from the Qualification Period. If the Day 1 pre-dose and Qualification 
Period measurements are all missing, then the last non-missing measurement from the Screening 
Period will be used as baseline. For lipids other than TG, missing baseline values will be imputed 
using the multiple imputation method described in Section 4.9.1.4 in the SAP. Note that if on 
Day 1, there are multiple pre-dose assessments, then the last assessment with non-missing value 
will be used as the Day 1 pre-dose assessment.  
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The baseline for platelet is defined as the average of all assessments prior to the first dose of 
Study Drug. 
The baseline for other measurements is defined as the last non-missing assessment prior to the 
first dose of Study Drug. 
The Month 6 lipid assessments are defined as the average of non-missing Weeks 25 and 27 
fasting assessments. The Month 12 lipid assessments are defined as the average of non-missing 
Weeks 51 and 53 fasting assessments. For both Month 6 and Month 12, if 1 of the 2 assessments 
is missing, then the other non-missing assessment will be used. 
4.2.3 
Analysis Visit Windows  
The efficacy measures of fasting lipid panel (TG, APOC-III, VLDL-C, remnant cholesterol, TC, 
non-HDL-C, apoB, HDL-C, LDL-C, and ApoA-1), including the data from both scheduled and 
unscheduled visits, will be mapped to analysis visits according to the visit windows in Table 1 
below.  
The intent of these visit windows is not to align with those prescribed for visit scheduling in the 
study protocol, but rather based on the protocol-defined target study day, to delineate mutually 
exclusive windows so that all efficacy assessments proximal to a particular study week can be 
integrated to best represent the patient’s status during that period of the study. Visits after 
Week 53 are part of the post-treatment assessment period and will be summarized by the visit 
label provided in the data. No visit windows are needed for the data of post-treatment visits.   
For lipid data, local lab data will not be used unless central lab assessments are not available at 
certain visit. When calculating the baseline and analysis endpoints, only if the data from central 
lab is missing, then the local lab data will be utilized. If there are multiple assessments within a 
visit window, the assessment nearest the target day will be used unless two assessments are 
equally near, in which case the average value will be used.   
If a patient discontinued early from the treatment period but attended applicable landmark visits 
to collect efficacy assessments, then those assessments should be mapped to analysis visits and 
utilized in the analyses as well, unless otherwise stated.   
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randomized subjects. The number and percentage of subjects who discontinued 
treatment or post-treatment follow-up related to COVID-19 will also be summarized. 
A by-subject listing of disposition data for randomized subjects will be provided. A separate 
disposition listing including eligibility criteria for screen failures will also be provided. 
4.4.2 
Protocol Deviations  
Protocol deviations will be recorded in the eCRF, where they will be classified as “minor” or 
“major”. All protocol deviations and major protocol deviations will be summarized by deviation 
category, by treatment group, total olezarsen treated, and overall, based on randomized subjects. 
The number and percentage of subjects with protocol derivation, in each deviation category and 
due to COVID-19 related impact will be provided for all protocol deviations or major protocol 
deviations in separate tables. All protocol deviations will be listed. 
Significant protocol deviations are defined as those deviations from the protocol likely to impact 
the perceived efficacy and/or safety of study treatments. The impact of significant protocol 
deviations on the efficacy and/or safety results will be investigated by assessing the robustness 
of the study results and conclusions to the choice of analysis set, both including and excluding 
data potentially affected by significant protocol deviations. Before unblinding, the data will be 
reviewed by the clinical group for identification of significant protocol deviations.  
4.5 
Demographic and Baseline Characteristics  
Demographic data and baseline characteristics will be summarized by treatment group, total 
olezarsen treated, and overall using descriptive statistics based on the FAS, PPS, and Safety Set, 
separately. 
Demographic data include, but are not limited to age, age group (< 65 years, ≥ 65 years), sex, 
ethnicity, race, height, weight, and body mass index (BMI). 
Key baseline laboratory parameters include baseline HbA1c and baseline lipids profile: fasting 
TG, apoC-III, TC, HDL-C, apoB, remnant cholesterol, VLDL-C, non-HDL-C, LDL-C and apoA-1.  
A by-subject listing of the demographic data and the baseline characteristics will be provided for 
randomized subjects. 
4.6 
Analysis Sets  
For purposes of analysis within this SAP, the following populations are defined: 
Full Analysis Set (FAS): All patients who are randomized and received any amount of Study 
Drug (olezarsen or placebo). The FAS represents the practically feasible intent-to-treat (ITT) 
population as delineated in International Conference on Harmonization (ICH) Guideline E9. This 
set will be used for the primary analysis of efficacy. 
Per Protocol Set (PPS): Subset of the FAS who received at least 5 monthly doses of Study Drug 
within the first 6 months of the Treatment Period, have a baseline fasting TG assessment, and 
who have no significant protocol deviations that could compromise the interpretation of efficacy. 
Significant protocol deviations will be determined prior to unblinding for statistical analysis. This 
set will be used for supportive inferences concerning efficacy.  
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Safety Set: All patients who are randomized and received any amount of Study Drug. This set 
will be used for all safety analyses. 
PK Set: All patients who are randomized and received any amount of olezarsen and have at least 
1 evaluable concentration result post-first dose. This set will be used for analysis of PK data. 
The number and percentage of subjects in each analysis set will be summarized by treatment 
group, total olezarsen treated, and overall based on randomized patients. 
A by-subject listing of analysis sets, including the inclusion/exclusion flag for each analysis set 
and reasons for exclusion from each analysis set, will be provided. 
4.7 
Medical History  
The medical history will be coded to System Organ Class (SOC) and Preferred Term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA). The final MedDRA version used will 
be designated in the clinical study report. The number and percentage of subjects reporting a 
medical history will be summarized by SOC, PT and by treatment group, total olezarsen treated, 
and overall, using the Safety Set.  
A by-subject listing of medical history will be provided. 
A separate table will be created for the targeted medical history based on the Safety Set. The 
number and percentage of patients with below targeted medical history terms will be summarized 
accordingly. A listing of targeted medical history will be provided. 
Cardiac-related history: 
• 
Atherosclerotic CV disease [ASCVD] 
o Coronary artery disease [CAD] 
 
Angiographic evidence of ≥ 50% Stenosis in 1 or more major epicardial 
coronary arteries 
 
Cardiac Ischemia on exercise stress test/imaging 
 
Coronary Artery calcium scan completed with a score >100 
 
Myocardial Infarction (MI) 
 
Percutaneous coronary intervention [PCI] 
 
CABG 
o Cerebrovascular Disease 
 
Ischemic Stroke  
 
Carotid Artery Disease defined by the ASCVD criterion 
• 
≥ 50% carotid artery stenosis 
• 
Carotid Endarterectomy 
• 
Carotid artery revascularization(s) other than Carotid 
Endarterectomy (either surgical or stenting) 
o Peripheral artery disease 
 
Peripheral Revascularization 
 
Aorto-iliac Revascularization 
 
Lower extremity amputations due to Peripheral Artery Disease 
 
Ankle-brachial index < 0.9 with symptoms of intermittent claudication 
 
Ankle-brachial index < 0.9 without symptoms of intermittent claudication 
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• 
TIA 
• 
Any Stroke 
• 
Hemorrhagic Stroke 
• 
Other Cerebrovascular disease  
• 
Unstable Angina 
• 
Heart failure 
• 
Current NYHA Class 
• 
Atrial fibrillation 
Other risk factors: 
• 
Diabetes mellitus Type 1 
o Duration (in years) of diabetes mellitus Type 1, duration being calculated as the 
year of informed consent from (ICF) minus the start year of the disease plus one. 
• 
Diabetes mellitus Type 2 
o Duration (in years) of diabetes mellitus Type 1, duration being calculated as the 
year of ICF minus the start year of the disease plus one. 
• 
Hypertension requiring pharmacologic treatment 
• 
Smoking 
o Current 
o Former 
• 
Chronic kidney disease 
o stage 
Medication history: 
• 
Statins 
o Reason not on statins 
• 
Any other lipid lowering therapy 
o Reason not on lipid lowering therapy 
Hematologic disorder history: 
• 
Bleeding diathesis or coagulopathy 
 Pancreatitis history: 
• 
Acute pancreatitis or any symptoms suggestive of pancreatitis with hospitalization 
• 
Acute pancreatitis or any symptoms suggestive of pancreatitis without hospitalization 
• 
Known Chronic Pancreatitis 
Previous Treatment: 
• 
Previous treatment with volanesorsen  
• 
Previous treatment with olezarsen  
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4.8 
Prior and Concomitant Medication  
Medication start and stop dates will be compared to the date/time of the first dose of study drug 
to allow medications to be classified as prior medication, and concomitant medication.  
Any medication taken prior to the first dose of study drug will be classified as a prior medication, 
regardless of whether continued while on treatment or not.  Any medication taken on or after the 
first dose of study drug will be classified as a concomitant medication.  
Partial or missing medication start and/or stop date(s) will be imputed by the following imputation 
rules: 
Missing or partial start date: 
• 
If year, month and day are all missing then assign the date of first dose of Study Drug 
• 
If month and day are missing and year is: 
o earlier than the year of the first dose of Study Drug then assign December 31 
o otherwise, assign January 1 
• 
If only day is missing, and month-year is: 
o earlier than the month-year of the first dose of Study Drug then assign the last 
day of the month 
o otherwise, assign the first day of the month 
Missing or partial end date: 
Imputation will be performed for the end date only if the day or month is missing (i.e., year is 
present): 
• 
If month and day are missing, then assign December 31 
• 
If only day is missing, then assign the last day of the month 
If the imputed start date is later than the imputed end date, then set the imputed start date to the 
imputed end date. 
Prior and concomitant medications will be coded using the World Health Organization - Drug 
Dictionary Enhanced (WHO-DDE) and summarized by Anatomical Therapeutic Chemical (ATC) 
drug class, preferred term (PT) and by treatment group, total olezarsen treated and overall based 
on the Safety Set. Actual versions of WHO-DDE used will be stated in the clinical study report. 
The number and percentage of patients in each of the following categories will also be 
summarized by treatment group, total olezarsen treated, and overall using the Safety Set:  
• 
Not taking statins at baseline 
o Initiated statins after study drug administration 
o Taking statins at baseline  
• 
Increased statin dose or switched to higher intensity after study drug administration 
All prior and concomitant medications will be listed based on the Safety Set. 
4.9 
Efficacy Evaluation  
The primary endpoint will be assessed on the FAS and PPS, with the former being the basis for 
the primary efficacy analysis. All the secondary endpoints will be assessed on the FAS. 
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4.9.1 
Analysis and Data Conventions  
4.9.1.1 
Hypothesis  
The null hypothesis of the primary analysis is that there is no difference between olezarsen and 
Placebo in the percent change in fasting TG from Baseline at Month 6. The alternative hypothesis 
is that there is a difference between olezarsen and Placebo in the percent change in fasting TG 
from Baseline at Month 6.   
Symbolically, this is expressed as follows: 
H(0) : µ(test) = µ(reference) 
H(1) : µ(test) ≠ µ(reference) 
4.9.1.2 
Multi-center Studies  
The term ‘Center’ will be used to define each investigator site. The study will be conducted at 
multiple centers in multiple countries. The data from all study centers will be pooled together for 
the statistical summaries. 
4.9.1.3 
Adjustments for Covariates  
The covariate will include the baseline stratification factor and baseline measurements.  
The baseline stratification factor will be classified as two categories below based on the base TG 
• 
Baseline TG ≥ 500 mg/dL (5.65 mmol/L) vs. < 500 mg/dL  
4.9.1.4 
Handling of Dropouts or Missing Data  
Multiple imputation for missing fasting TG at month 6 and/or month 12: 
As the randomization stratification factor, the fasting TG at qualification visit will not be missing. 
Therefore, the baseline fasting TG for all randomized patients will not be missing as the fasting 
TG at qualification visit will be used to calculate the baseline fasting TG (refer to Section 4.2.2). 
Patients with a missing fasting TG at Months 6 and/or 12 will have missing values multiply imputed 
based on the known assessments from the retrieved dropouts (e.g., for Month 6, the retrieved 
dropouts include those patients who discontinue treatment before Week 25 but still have 
assessments at Week 25 or 27; for Month 12, the retrieved dropouts include those patients who 
discontinue treatment before Week 51 but still have assessments at Week 51 or 53), if there are 
a sufficient number of retrieved dropouts. The imputation model contains the following variables: 
baseline fasting TG, fasting TG at each post-baseline visit and the multiple imputation will be 
stratified by treatment group (Schafer 1997; Schafer 1999).  
If there is no sufficient number of retrieved dropouts, missing TG value after treatment 
discontinuation at Month 6 or Month 12 will be imputed using a “wash-out” (Jump to Reference, 
J2R) multiple imputation approach. With the approach, patients treated with olezarsen who 
discontinue treatment will have missing TG values after the last “observed value” multiply imputed 
based on baseline fasting TG and the imputation model for the placebo group. Patients in the 
placebo group who discontinue the treatment will have missing TG values multiply imputed using 
the baseline fasting TG, fasting TG values at post-baseline visits from the placebo group. 
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The Markov Chain Monte Carlo (MCMC) method will be used under the multivariate normality 
assumption to impute the missing values by treatment group. The variable list for imputations will 
include the baseline value, as well as all available post-baseline value. To conform to the 
multivariate normality assumption, baseline and post-baseline fasting TG will be natural 
log-transformed before the imputation process, the data will be back transformed to create the 
imputed data set after the imputation. The SAS procedure PROC MI will be used to create 
1000 imputed datasets. The first 100 imputed datasets with imputed values within the analytical 
measuring range will be chosen from 1000 imputed datasets for the analysis.  
Default EM algorithm will be used to derive a set of initial parameter estimates for MCMC method. 
A non-informative prior (Jeffreys’ prior) will be used to derive the posterior distribution of the 
parameters.  
The following pseudo SAS code and seed (2438291) will be used to perform the multiple 
imputation:  
Step 1, using PROC MI to generate 1000 imputations: 
/****************************************************************************     */ 
/* Note:                                                                          */ 
/* 
baseline = baseline fasting TG                                             */ 
/* 
impute = the iteration number in the multiple imputation                   */ 
/* 
trtpn = Treatment group: 0=Placebo, 1= olezarsen 50 mg, 2 = olezarsen 80 mg*/ 
/**********************************************************************************/ 
proc mi data = TG seed = 2438291 nimpute = 1000 out=TGIM; 
transform log(baseline) log(week5) log(week9) log(week13) log(week17) 
log(week21) log(month6) log(week29) log(week37) log(week45) log(month12);  
      mcmc; 
  var baseline week5 week9 week13 week17 week21 month6 week29 week37 week45 
month12; 
  by trtpn; 
       run;  
Step 2, extract placebo data, fit a GLM model using log transformed data for each imputation 
and get parameter estimates: 
proc glm data=pla_mar;  
          by paramcd imputation_; 
          model AVAL_log=base_log avisitn_interval/solution; 
run; 
Step 3, for patients in the active arm, remove the imputed data post last “observed value”, apply 
the parameter estimates calculated from step 2 to active treatment arms and back transformed 
the data to create the 1000 imputation datasets. 
Step 4: Set the dataset from step 3 and the subset of placebo dataset (the dataset used in step 
2) together then choose the first 100 imputation dataset with imputed values within the analytical 
measuring range. 
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Multiple imputation for missing fasting lipids (excluding TG) at baseline and Month 
6/Month 12: 
For other lipid data (apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, HDL-C, TC, apoB, 
LDL-C, and apoA-1), a two-stage multiple imputation approach will be utilized to impute the 
missing values at baseline, Months 6 and Month12 if baseline is missing for at least one 
randomized patient for given lipid parameter.  
First, the missing baseline fasting lipid value will be multiply imputed based on the observed 
baseline assessments from other patients. The MCMC method (Schafer 1997; Schafer 1999) will 
be used to impute the missing values. The imputation model will include baseline fasting lipid 
value and baseline stratification factor (i.e., baseline fasting TG ≥ 500 mg/dL (yes/no). The 
baseline lipid value will be natural log-transformed before the imputation process, the data will be 
back transformed to create the imputed data set after the imputation. The SAS procedure PROC 
MI will be used to create 1000 imputed datasets. 
The following pseudo SAS code and seed (2438291) will be used to perform the multiple 
imputation for missing lipid data at baseline: 
/************************************************************************************/ 
/*  Note:                                                                           */             
/*  baseline = baseline fasting lipid value                                         */ 
/*  stratt = Baseline TG >= 500 mg/dL (5.65 mmol/L) Yes/No                  */ 
/************************************************************************************/ 
   proc mi data = adeff seed = 2438291 nimpute = 1000 out= adeff2; 
transform log(baseline);  
            mcmc;  
    var stratt baseline; 
   run; 
The imputed baseline values will be merged with the observed post baseline data and used for 
the second stage of imputation. 
In the second stage of imputation, the missing lipid value at Months 6 and/or 12 will be imputed 
using similar method described above for missing fasting TG at month 6 and/or month 12, with 
an imputation model that contains the following variables: baseline fasting lipid value, fasting lipid 
value at each post-baseline visits and baseline stratification factor. The multiple imputation will be 
stratified by treatment group (Schafer 1997; Schafer 1999). 
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The following pseudo SAS code and seed (2438291) will be used for the second stage of 
imputation: 
/************************************************************************************/ 
/*  Note:                                                                           */ 
/*  baseline = baseline lipid parameter                                             */ 
/*  trtpn = treatment group: 0=placebo, 1=olezarsen 50 mg, 2=olezarsen 80 mg        */ 
/*  _imputation_ = the iteration number in the stage 1 imputation                   */ 
/* stratt = baseline TG >= 500 mg/dL (5.65 mmol/L) Yes/No                   */         
/************************************************************************************/ 
proc sort data=adeff2;  
   by _imputation_;  
run; 
proc mi data=adeff2 (where=(trtpn=0)) seed=2438291 nimpute=1 out=imputed; 
/*repeat the procedure for each treatment group by replacing trtpn category in the 
where option*/ 
   transform log(baseline) log(week5) log(week9) log(week13) log(week17) log(week21) 
log(month6) log(week29) log(week37) log(week45)  log(month12);   
   mcmc; 
   var baseline stratt week5 week9 week13 week17 week21 month6 week29 week37 week45 
month12; 
   by _imputation_; 
run; 
 
For lipid parameters with no missing data at baseline, the baseline imputation will not be 
performed. The second stage of imputation will be performed to create 1000 imputed datasets. 
The following pseudo SAS code and seed (2438291) will be used for multiple imputation: 
/************************************************************************************/ 
/*  Note:                                                                           *               
/*  baseline = baseline lipid parameter                                             */ 
/*  trtpn = treatment group: 0=placebo, 1=olezarsen 50 mg, 2=olezarsen 80 mg        */ 
/*  stratt = baseline TG >= 500 mg/dL (5.65 mmol/L) Yes/No                  */  
/************************************************************************************/ 
 
proc mi data=adeff seed=2438291 nimpute=1000 out=adeff2;  
   transform log(baseline) log(week5) log(week9) log(week13) log(week17) log(week21) 
log(month6) log(week29) log(week37) log(week45) log(month12);   
   mcmc; 
   var stratt baseline week5 week9 week13 week17 week21 month6 week29 week37 week45      
month12; 
by trtpn; 
run; 
 
The Step 2, 3 and 4 similar to that for TG imputation with an additional factor of baseline TG 
stratification factor will be used to create 100 imputation datasets. 
4.9.1.5 
Multiple Comparisons/Multiplicity  
The multiplicity will be controlled by using a hierarchical ranking strategy in the following testing 
sequence. All tests will be conducted at a two-sided alpha level of 0.05. For the primary endpoint 
family, the 2 treatment arms will be compared against placebo using the hierarchical testing 
procedure, in which the olezarsen 80 mg treatment group will be compared to the placebo at the 
2-sided alpha level of 0.05, if the comparison is statistically significant (p < 0.05), then the 
olezarsen 50 mg treatment group is compared against the placebo at the alpha level of 0.05.  If 
the comparison of the olezarsen 80 mg treatment group to placebo group is not statistically 
significant, then the comparison of the olezarsen 50 mg treatment group against placebo and all 
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secondary endpoints will be considered exploratory. The order of the testing on the secondary 
endpoints is outlined below. The endpoint ranked as first will be tested and the difference will be 
declared statistically significant if the p value is less than 0.05. In case that the difference for the 
first endpoint is statistically significant, the endpoint ranked as second will be tested, and the 
difference will be declared statistically significant if the p-value is less than 0.05. The testing will 
continue as long as the previously ranked endpoint is statistically significant. If the secondary 
endpoints are not evaluated as a part of the hierarchical testing procedure due to previously 
ranked endpoint was not statistically significant, the statistical tests will be reported and 
interpreted in a descriptive manner.  
1. Primary endpoints family: 
• 
Primary endpoint: Comparison of percent changes in fasting TG from Baseline to Month 
6 between olezarsen 80 mg treatment group and placebo in the FAS 
• 
Primary endpoint (not co-primary endpoint): Comparison of percent changes in fasting 
TG from Baseline to Month 6 between olezarsen 50 mg treatment group and placebo in 
the FAS 
2. Secondary endpoints will be tested in the FAS according to the following sequence:  
• 
Comparison of percent change in fasting TG from Baseline to Month 12 between 
olezarsen 80 mg and placebo group  
• 
Comparison of percent change in fasting TG from Baseline to Month 12 between 
olezarsen 50 mg and placebo group  
• 
Comparison of percent change in fasting apoC-III from Baseline to Month 6 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting apoC-III from Baseline to Month 12 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting apoC-III from Baseline to Month 6 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting apoC-III from Baseline to Month 12 between 
olezarsen 50 mg and placebo group 
• 
Comparison of proportion of patients who achieve fasting TG < 150 mg/dL at Month 6 
between olezarsen 80 mg and placebo group in the subgroup of FAS with baseline 
fasting TG < 500 mg/dL 
• 
Comparison of proportion of patients who achieve fasting TG < 150 mg/dL at Month 12 
between olezarsen 80 mg and placebo group in the subgroup of FAS with baseline 
fasting TG < 500 mg/dL 
• 
Comparison of percent change in fasting VLDL-C from Baseline to Month 6 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting VLDL-C from Baseline to Month 12 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting VLDL-C from Baseline to Month 6 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting VLDL-C from Baseline to Month 12 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting non-HDL-C from Baseline to Month 6 between 
olezarsen 80 mg and placebo group 
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• 
Comparison of percent change in fasting non-HDL-C from Baseline to Month 12 
between olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting non-HDL-C from Baseline to Month 6 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting non-HDL-C from Baseline to Month 12 
between olezarsen 50 mg and placebo group 
• 
Comparison of proportion of patients who achieve fasting TG < 150 mg/dL at Month 6 
between olezarsen 50 mg and placebo group in the subgroup of FAS with baseline 
fasting TG < 500 mg/dL 
• 
Comparison of proportion of patients who achieve fasting TG < 150 mg/dL at Month 12 
between olezarsen 50 mg and placebo group in the subgroup of FAS with baseline 
fasting TG < 500 mg/dL 
• 
Comparison of percent change in fasting HDL-C from Baseline to Month 6 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting HDL-C from Baseline to Month 12 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting HDL-C from Baseline to Month 6 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting HDL-C from Baseline to Month 12 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting remnant cholesterol from Baseline to Month 6 
between olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting remnant cholesterol from Baseline to Month 12 
between olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting remnant cholesterol from Baseline to Month 6 
between olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting remnant cholesterol from Baseline to Month 12 
between olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting apoB from Baseline to Month 6 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting apoB from Baseline to Month 12 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting apoB from Baseline to Month 6 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting apoB from Baseline to Month 12 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting ApoA-1 from Baseline to Month 6 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting ApoA-1 from Baseline to Month 12 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting ApoA-1 from Baseline to Month 6 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting ApoA-1 from Baseline to Month 12 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting LDL-C from Baseline to Month 6 between 
olezarsen 80 mg and placebo group 
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• 
Comparison of percent change in fasting LDL-C from Baseline to Month 12 between 
olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting LDL-C from Baseline to Month 6 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting LDL-C from Baseline to Month 12 between 
olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting total cholesterol from Baseline to Month 6 
between olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting total cholesterol from Baseline to Month 12 
between olezarsen 80 mg and placebo group 
• 
Comparison of percent change in fasting total cholesterol from Baseline to Month 6 
between olezarsen 50 mg and placebo group 
• 
Comparison of percent change in fasting total cholesterol from Baseline to Month 12 
between olezarsen 50 mg and placebo group 
• 
Comparison of proportion of patients who achieve fasting TG < 500 mg/dL at Month 6 
between olezarsen 80 mg and placebo in the subgroup of FAS with baseline fasting TG 
≥ 500 mg/dL 
• 
Comparison of proportion of patients who achieve fasting TG < 500 mg/dL at Month 12 
between olezarsen 80 mg and placebo in the subgroup of FAS with baseline fasting TG 
≥ 500 mg/dL 
• 
Comparison of proportion of patients who achieve fasting TG < 500 mg/dL at Month 6 
between olezarsen 50 mg and placebo in the subgroup of FAS with baseline fasting TG 
≥ 500 mg/dL 
• 
Comparison of proportion of patients who achieve fasting TG < 500 mg/dL at Month 12 
between olezarsen 50 mg and placebo in the subgroup of FAS with baseline fasting TG 
≥ 500 mg/dL 
• 
Comparison of adjudicated acute pancreatitis event rate during the Treatment Period 
between pooled olezarsen treatment group and placebo  
• 
Comparison of adjudicated acute pancreatitis event rate during the Treatment Period 
between pooled olezarsen treatment group and placebo in the subset of FAS with ≥ 2 
events of adjudicated acute pancreatitis in 5 years prior to enrollment in FAS 
4.9.1.6 
Interim Analyses  
There is no interim analysis planned for the study. 
4.9.1.7 
Examination of Subgroups  
Subgroup analyses of the primary efficacy and applicable secondary endpoints will be made to 
assess consistency of analysis results over subgroups. The subgroups include but are not limited 
to:  
• 
Baseline fasting TG ≥ 500 mg/dL vs. < 500 mg/dL 
• 
Baseline fasting TG ≥ 200 mg/dL vs. < 200 mg/dL 
• 
age groups (< 65, ≥ 65 years) 
• 
race (White vs non-White)  
• 
Sex (male, female) 
• 
ethnicity (Hispanic or Latino vs. Not Hispanic or Latino) 
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• 
Baseline BMI (< 25, 25 to < 30, 30 to < 40, ≥ 40 kg/m2) 
• 
diabetic status (diabetic vs non-diabetic) 
• 
Baseline Hemoglobin A1C (HbA1c): < 6.5 vs. ≥ 6.5 
• 
Baseline background therapies (lipid-modifying therapy versus none; statins versus no 
statins; Fibrates vs. no Fibrates) 
• 
Previous treatment with volanesorsen: Yes vs. No 
4.9.2 
Primary Efficacy Variable  
The primary efficacy variable is the percent change from Baseline to Month 6 (average of 
Weeks 25 and 27) in fasting TG.  
4.9.2.1 
Primary Analysis  
The primary efficacy analysis will take place after the last patient has completed the Week 53/ET 
visit and the database has been locked. 
The primary analysis of the primary endpoint is to compare the percent change from Baseline to 
Month 6 in fasting TG between each olezarsen treatment group vs. placebo group using the FAS.  
If patients have intercurrent event(s) before Week 25, e.g., treatment discontinuation, use of 
additional medication, changes in background or concomitant treatments, the Treatment Policy 
strategy will be implemented, the patients’ assessments post intercurrent events will continue to 
be collected. All assessments including those post the intercurrent events will be utilized in the 
analysis. Patients with a missing TG value at Month 6 will have TG imputed, details are described 
in Section 4.9.1.4. 
The attributes and description of the estimands are provided in the tables below: 
Treatments 
• 
olezarsen 80 mg  
• 
placebo 
Participant 
Population 
Patients with hypertriglyceridemia and atherosclerotic cardiovascular 
disease (ASCVD) (established, or at increased risk for), or with severe 
hypertriglyceridemia (SHTG) as defined by protocol eligibility criteria 
Variable 
Percent change from Baseline to Month 6 (average of Weeks 25 and 
27) in fasting TG 
Intercurrent events 
(ICEs) and 
strategies 
• 
Discontinuation of study treatment prior to Week 25 
Treatment policy strategy 
• 
Disallowed concomitant therapy/procedure prior to Week 25 
Treatment policy strategy 
Population-level 
summary 
Difference in means of percent change between olezarsen 80 mg and 
placebo in the FAS 
Description of 
estimand 
The difference in means of percent change from Baseline to the Month 
6 in fasting TG between olezarsen 80 mg and placebo (regardless of 
early treatment discontinuation, use of additional medication, or change 
in background or concomitant treatments) in patients with 
hypertriglyceridemia and ASCVD (established, or at increased risk for), 
or with SHTG 
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For each of the 100 imputed datasets obtained from Section 4.9.1.4, the percent change from 
Baseline to Month 6 in fasting TG will be compared between olezarsen treatment groups and 
placebo using an analysis of covariance (ANCOVA) model that assumes unequal variance with 
precent change from Baseline to Month 6 in fasting TG as the dependent variable, treatment 
group (olezarsen 80 mg, olezarsen 50 mg, or Placebo) as factor, and natural log-transformed 
baseline fasting TG as a covariate. 
The pseudo SAS code of ANCOVA:  
/***************************************************************************      */ 
/* Note:                                                                          */ 
/* 
baseline = baseline TG                                                     */ 
/* 
impute = the iteration number in the multiple imputation                   */ 
/* 
trtpn = Treatment group: 0=Placebo, 1= olezarsen 50 mg, 2 = olezarsen 80 mg*/ 
/* 
pchg = percent change TG from baseline to Month 6                          */ 
/***************************************************************************      */ 
   data TG; set TG; 
      logbase = log(baseline);   /* log transformed baseline*/       
   proc mixed data = TG; 
      by impute; 
      class trtpn; 
      model pchg = trtpn logbase/ ddfm=satterth; 
      lsmeans trtpn/e diff cl; 
      estimate ‘olezarsen 50 mg vs Placebo’ trtpn -1 1 0;  
      estimate ‘olezarsen 80 mg vs Placebo’ trtpn -1 0 1; 
   run; 
The model will provide an estimate of Least Squares (LS) Mean of percent change from 
baseline in fasting TG for each treatment group as well as the treatment differences relative to 
the placebo group and the corresponding standard error. 
The estimates from the fitted models for each of the 100 imputed datasets will be combined to 
provide an overall estimate with corresponding CIs and p-value (Little and Rubin 2002). The 
following pseudo SAS code will be used to estimate corresponding CIs and p-value:  
   proc mianalyze data=diff; 
      modeleffects estimate; 
      stderr stderr;  
   run;  
4.9.2.2 
Sensitivity Analysis of Primary Endpoint  
The following sensitivity analyses of the primary endpoint will be conducted to assess the 
robustness of the primary analysis result. 
Sensitivity Analysis 1:  
The primary analysis with ANCOVA model for percent change in fasting TG from Baseline to 
Month 6 will be repeated in the PPS.  
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Sensitivity Analysis 2 - Completer Set:  
The primary efficacy analysis with ANCOVA model for percent change in fasting TG from Baseline 
to Month 6 will be repeated in a subset of patients in the FAS with no missing TG value at baseline 
and Month 6.  
Sensitivity Analysis 3:  
A nonparametric Wilcoxon rank-sum test will be performed on the percent change in TG from 
baseline to Month 6 based on FAS. Missing data will be handled using the same multiple 
imputation method as the primary analysis. The estimates from the fitted model for each of the 
100 imputed datasets will be combined to provide an overall Hodges-Lehmann estimator of the 
location shift and corresponding 95% CI between olezarsen 80 mg group and placebo group. The 
same approach will be used for comparison between olezarsen 50 mg group and placebo group. 
The example SAS code can be found below: 
/*************************************************************************/ 
/* Note:                                                                 */       
/*  pchg = percent change of TG from baseline to Month 6                 */       
/*  impute = the iteration number in the multiple mutation               */       
/*  trtpn = treatment group: 0=placebo, 1=olezarsen 80 mg                */       
/*************************************************************************/ 
proc npar1way data= TGIM hl alpha=0.05; 
 
class trtpn; 
 
var pchg; 
 
by impute; 
run; 
Sensitivity Analysis 4 - Tipping point analysis using FAS: 
An additional sensitivity analysis using the 2-dimensional tipping-point approach will be conducted 
in the FAS to assess the impact of missing data on the result of the primary analysis. The 
sensitivity analysis will be conducted as follows using the imputed data based on the primary 
imputation approach as described in Section 4.9.1.4 in the SAP: 
1. For the placebo group, a positive constant shift (δc,, %) will be added to or subtracted 
from the percent change of imputed TG values at the primary time point. The shift will 
gradually increase. 
2. For each value of the placebo shift parameter, a positive constant shift (δt, %) will be 
added to or subtracted from the percent change of imputed TG values at the primary 
time point in the active treatment groups. The shift will be increased in a repeated 
process until the treatment effect is no longer significant at 0.05 level in step 5 below.  
3. For each of the 100 imputed datasets, the same ANCOVA model as described for the 
primary analysis of the primary endpoint will be fitted to estimate treatment differences 
and standard errors. 
4. The 100 sets of estimates will be combined with SAS PROC MIANALYZE as described 
in Section 4.9.1.4 in the SAP.  
5. Steps 1 to 4 will be repeated with different values of the shift parameters until the tipping 
points are reached. 
Values of δc and δt will be determined post-hoc in order to define reasonable increments. 
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Sensitivity Analysis 5 - Exploring the robustness of the primary analysis (FAS): 
A few sensitivity analyses using controlled imputations (pattern mixture models (PMM)) with 
ANCOVA will be conducted in the FAS to assess the impact of alternative missing data 
assumptions on the robustness of the primary analysis results.  
• 
Patients treated with olezarsen who discontinue the treatment due to AE (i.e., informative 
missing), their missing TG data after the last “observed value will be multiply imputed 
using the copy increment from reference (CIR) approach (Carpenter et al. 2013)7 based 
on the estimates from of the placebo patients. The assumption is when a patient 
discontinues treatment due to informative missing, they continue to take advantage of 
their previous therapy, but from discontinuation onwards he/she would progress in the 
same way as the patients in the placebo group (i.e., parallel to the profile for the placebo 
group). For patients who discontinue due to other reasons and all patients from the 
placebo group, their missing data will be treated as non-informative missing, and data will 
be multiply imputed based on the distribution of their own arm. The reason for this is that 
it is assumed those patients would have proceeded in the future, in a comparable way to 
similar patients (with similar baseline and covariates) in their own treatment who did 
remain in the trial. The analysis will be conducted in the FAS. Baseline and post-baseline 
fasting TG will be natural log-transformed before the imputation process, the data will be 
back transformed to create the imputed data set after the imputation. 
• 
All patients treated with olezarsen who discontinue the treatment will have missing TG 
values after the last “observed value multiply using the CIR approach based on the 
estimates from the placebo patients. Missing TG for placebo patients will be imputed 
using the MI method as the primary analysis. 
Baseline and post-baseline fasting TG will be natural log-transformed before the imputation 
process, the data will be back transformed to create the imputed data set after the imputation. 
Sensitivity Analysis 6 - ANCOVA model using log-transformed data (FAS) 
The percent change from Baseline to Month 6 in fasting TG between each olezarsen treatment 
group (olezarsen 80 mg, olezarsen 50 mg) vs. pooled placebo will be compared using ANCOVA 
model with log(y/x) as dependent variable, where y is the value of fasting TG at Month 6, x is the 
baseline value of fasting TG; treatment group as factor and nature log-transformed baseline 
fasting TG as a covariate. The model will provide an estimate of log post-baseline to baseline 
ratio for each treatment group as well as the ratios relative to the pooled placebo group and the 
corresponding SEM. The log post-baseline to baseline ratios will be converted back to the original 
ratio scale. The percent change from baseline for each treatment group will then be calculated 
based on the estimated ratio as 100% * (ratio -1). Similarly, the estimated upper and lower CIs 
for the ratio can be calculated as 100% * (CI - 1). Patients with missing fasting TG value at Month 6 
will have fasting TG value multiply imputed using the multiple imputation methods described in 
Section 4.9.1.4 in the SAP.  
4.9.3 
Secondary Efficacy Variables  
To control the type I error, a hierarchical ranking strategy will be employed with the sequence of 
endpoints defined as in Section 4.9.1.5. 
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4.9.3.1 
Percent Change in Fasting TG From Baseline at Month 12  
The percent change in fasting TG from Baseline to Month 12 (average of Week 51 and Week 53) 
in the FAS will be analyzed in the same way as for the primary endpoint. 
The same set of sensitivity analyses (sensitivity analysis 1 to sensitivity analysis 6) and subgroup 
analysis as for the primary endpoint will be conducted for the percent change in fasting TG from 
Baseline to Month 12. 
4.9.3.2 
Proportion of Patients Who Achieve Fasting TG < 150 mg/dL at Month 6 and at 
Month 12 in the Subgroup of Patients with Baseline fasting TG < 500 mg/dL  
The proportion of patients who achieve fasting TG < 150 mg/dL (1.69 mmol/L) at Month 6 and 
Month 12 in the subset of FAS with Baseline fasting TG < 500 mg/dL (5.65 mmol/L) will be 
compared between each olezarsen treatment group and placebo group using a logistic regression 
model with the treatment group as the factor, and natural log-transformed baseline fasting TG as 
a covariate. Missing TG values will be imputed using the same multiple imputation method as the 
primary analysis of the primary endpoint. For each of the 100 imputed datasets obtained from 
Section 4.9.1.4, the logistic regression model described above will be fitted and the estimates 
from each of 100 fitted model will be combined to provide an overall odds ratio with corresponding 
CIs and p-value. 
 Sensitivity Analysis 1:  
An additional sensitivity analysis will be conducted in the subgroup of FAS with Baseline fasting 
TG < 500 mg/dL, in which all patients who have missing data due to discontinuation will be 
considered as non-responders. 
Sensitivity Analysis 2:  
A 2-dimensional tipping-point analysis will be conducted in the subgroup of FAS with Baseline 
fasting TG < 500 mg/dL using the imputed data based on the primary imputation approach as 
described in Section 4.9.1.4 in the SAP. Similar to the sensitivity analysis 5 for the primary 
endpoint, a positive constant shift values (%) will be added to or subtracted from the percent 
change of the imputed TG values at each time point of interest until the tipping points are reached. 
4.9.3.3 
Percent Change in Fasting ApoC-III, VLDL-C, Remnant Cholesterol, Non-HDL-C, HDL-C, 
TC, ApoB, LDL-C, and ApoA-1 From Baseline at Month 6 and at Month 12  
The percent change in fasting apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, HDL-C, TC, 
apoB,  LDL-C, and apoA-1 from Baseline to Months 6 and Month 12 in the FAS will be analyzed 
in  the way similar to that for the primary endpoint using an ANCOVA model with precent change 
from Baseline to Month 6 or Month 12 in fasting value as the dependent variable, treatment group 
(olezarsen 80 mg, olezarsen 50 mg, or Placebo) and baseline stratification factor as factors, and 
natural log-transformed baseline value as a covariate. 
The sensitivity analyses using the imputation models as described in sensitivity analysis 3 and 5 
for the primary endpoint will be conducted. 
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4.9.3.4 
Proportion of Patients Who Achieve Fasting TG < 500 mg/dL at Month 6 and at 
Month 12 in the Subgroup of Patients with Baseline fasting TG ≥ 500 mg/dL  
The proportion of patients who achieve fasting TG < 500 mg/dL at Month 6 and Month 12 will be 
analyzed in the same way as the proportion of patients who achieve fasting TG < 150 mg/dL. It 
will be conducted in the subset of FAS with baseline fasting TG ≥ 500 mg/dL. Tipping point 
analysis will not be performed. 
4.9.3.5 
Adjudicated Acute Pancreatitis Event Rate During the Treatment Period in the FAS  
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis and as outlined in the PAC. These events will be categorized 
by the various criteria to be one of the following: 1) documented pancreatitis, 2) probable 
pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate, and 5) no diagnosis of acute 
pancreatitis. For the purposes of data analysis, events that are documented, probable or possible 
are to be considered adjudicated acute pancreatitis. A listing will be provided to display each 
adjudicator’s and the final adjudication committee’s classification results for each event. The 
adjudicated acute pancreatitis event rates will be compared between pooled olezarsen treatment 
and placebo group using a Negative Binomial regression model or Poisson regression model with 
the treatment group and natural log transformed baseline fasting TG as the factors, and number 
of adjudicated acute pancreatitis events in 5 years prior to the enrollment as a covariate. The 
logarithm of time in year that each patient observed during the Treatment Period will be used as 
an offset variable.  
From the models, the mean rate and SEM for each treatment group as well as the mean rate ratio 
relative to the placebo group and corresponding 95% CIs will be estimated. The p-value of 
Wald-based chi-square test will also be reported. 
Week 53 is defined as Day 379 (scheduled visit day plus a 14-day window) or the last contact 
date within the study, whichever is earlier. If patients have intercurrent event(s) before Week 53, 
the Treatment Policy strategy will be implemented, the pancreatitis events occurred post 
intercurrent events will continue to be collected. All adjudicated pancreatitis events including those 
post the intercurrent events will be included in the analysis. For patients who discontinued the 
treatment early and were lost to follow-up before Week 53, the pancreatitis event rate will be 
adjusted by the length of observation time in the analysis model. 
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The sample SAS code for the Negative Binomial regression model can be found below: 
/************************************************************************************/ 
/* Note*/                                                                             
/*  logbase     = log transformed baseline TG                                       */ 
/*  trtpn = treatment group: 0=pooled placebo, 1=olezarsen 80 mg or 50 mg           */ 
/*  numevent = number of adjudicated acute pancreatitis events                      */ 
/*  num5year = number of adjudicated acute pancreatitis events in 5 years prior to  */ 
/*             the enrollment                                                       */ 
/************************************************************************************/ 
 
data pan; set pan; 
   logtime = log(years); 
run; 
 
proc genmod data=pan; 
   class trtpn; 
   model numevent = trtpn  logbase  num5year/dist=negbin link=log 
      offset = logtime; 
   /* update “dist=negbin” to “dist=poisson” for Poisson regression model*/ 
   lsmeans trtpn/diff cl exp ilink; 
run; 
In the case of not enough acute pancreatitis events to perform the model-based analysis, the 
number and percentage of subjects with the acute pancreatitis event along with the two-sided 
95% exact CI using Clopper- Pearson methodology will be summarized based on FAS. Fisher’s 
exact p-value will also be provided. 
4.9.3.6 
Adjudicated Acute Pancreatitis Event Rate during the Treatment Period in the Subset 
of FAS with ≥ 2 Events of Adjudicated Acute Pancreatitis in 5 Years Prior to Enrollment  
The data will be analyzed in the same way as described in Section 4.9.3.5. 
4.10 Safety Evaluation  
All safety summaries will be based upon the Safety Set. By-visit safety data will be presented 
using visit label as recorded on the eCRF per Schedule of Procedures in Appendix A of the 
protocol.  
4.10.1 Extent of Exposure and Treatment Compliance  
The duration of exposure to olezarsen will be calculated as follows:  
• 
Treatment exposure (days) = date of last Study Drug administration – date of first 
administration + 28 
• 
Treatment exposure (months) = Treatment exposure (days)/30 
• 
Treatment Compliance (%) = (actual total dose injected [mg]) / (expected total dose to 
be administered during the treatment period [mg]) × 100. 
Note that for patients who early terminated from treatment, denominator should be based on the 
total doses expected (mg) until discontinuation. 
The following summaries will be provided by treatment group and olezarsen treated and listed 
based on Safety Set: 
• 
A summary of the treatment exposure in both days and months, total number of doses 
administered, and the total amount of study drug received (mg) 
• 
A summary of treatment compliance (%). 
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• 
Number of patients with dose interruption, dose interruption due to AE, and number of 
patients with study drug reduced. 
• 
Descriptive summary of number of days of dose interruption 
The following listings will be provided: 
• 
A by-subject listing of administration of study drug 
• 
A by-subject listing of treatment compliance (%) 
4.10.2 Adverse Events  
4.10.2.1 
Definition of Treatment-Emergent Adverse Event (TEAE)  
TEAEs are defined as adverse events that occurred on or after the first administration of 
Study Drug or worsened relative to the pre-treatment state. Note that imputed dates will be used 
for defining TEAEs. 
In addition, if severity of an AE changes during the study, a separate AE will be recorded for each 
severity on the AE CRF. The “first” and “second” AEs will be defined based on AE start date, and 
AE start date of the second record will be the same as AE stop date of the first record. AE severity 
(mild/moderate/severe) should be compared pairwise between these linked events when defining 
TEAEs. Consider 2 cases below:   
Case 1:  The first AE record in the pair occurs before first dosing, and the second AE 
record occurs after first dosing.   
If the AE severity of the second record is worse than that of the first record, then only the 
second AE is deemed as a TEAE.  Otherwise, neither record is considered as TEAE. 
Case 2:  Both AE records in the pair occur after first dosing.   
The worst AE will be deemed as a TEAE.  
All TEAEs identified based on the rules above will be summarized in the event number analysis. 
4.10.2.2 
Analysis for TEAEs  
All AEs will be coded to SOC and PT using the MedDRA. The final MedDRA version used will be 
designated in the clinical study report. The frequency and incidence of AEs will be summarized 
by SOC and PT. The SOCs will be presented in alphabetical order, and the PTs will be presented 
in descending frequency order within each SOC. Subjects reporting more than one AEs will be 
counted only once for each level of summation (most severe incident for the severity tables and 
most related incidence for the relationship tables).   
The frequency of patients with any incidences of AEs and the number of events will be presented 
by treatment group and total olezarsen treated for the following summaries: 
• 
Any TEAEs by SOC and PT 
• 
Any TEAEs by PT 
• 
TEAEs related to Study Drug by SOC and PT. Related is defined as “Related”, 
“Possible”, or missing relationship to Study Drug 
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• 
Any TEAEs by maximum severity, SOC and PT. At each severity level of subject 
summarization, a subject is classified according to the highest reported severity if the 
subject reported one or more events. TEAEs with missing severity will be categorized as 
“Missing” for this summary. 
• 
TEAEs related to Study Drug by severity, SOC, and PT 
• 
Serious TEAEs by SOC and PT 
• 
Serious TEAEs related to Study Drug by SOC and PT 
• 
Serious TEAEs related to Study Drug by SOC and PT 
• 
Serious TEAEs by severity 
• 
Serious TEAEs related to study drug by severity 
• 
TEAEs leading to permanent Study Drug discontinuation by SOC and PT 
• 
TEAEs related to Study Drug leading to permanent Study Drug discontinuation by SOC 
and PT 
• 
TEAEs leading to death by SOC and PT 
• 
TEAE with an incidence rate > 5% in any treatment group by PT  
• 
Non-serious TEAE with an incidence rate > 5% in any treatment group by PT 
An overall summary of frequency and incidence of AEs of above unique categories will be 
provided by treatment group and total olezarsen treated. By-subject listing of all AEs will be 
provided, in which non-treatment emergent AEs will be included and be noted. The following 
additional listings will be provided for TEAEs unless otherwise specified. 
• 
Listing of treatment-emergent SAEs 
• 
Listing of TEAEs related to study drug 
• 
Listing of TEAEs leading to discontinuation of Study Drug 
• 
Listing of all deaths 
To define TEAEs, the algorithm in Section 4.10.2.3 will be applied to impute missing or partial 
start date or end date. Original reported dates will be used for listings. 
4.10.2.3 
Missing Date for Adverse Events  
For AEs, the following imputation rules will be applied to impute missing dates under conservative 
principles. The imputed dates will be used for defining TEAEs. 
For start dates: 
• 
If year, month and day are all missing, then assign the date of first dose of Study Drug. 
• 
If month and day are missing and year is: 
o the same as the year of the first dose of Study Drug, then assign the month-day 
of first Study Drug 
o earlier than the year of the first dose of Study Drug, then assign December 31 
o after the year of the first dose of Study Drug, then assign January 1 
• 
If only day is missing, and month-year is: 
o the same as the month-year of the first dose of Study Drug, then assign the day 
of first Study Drug 
o earlier than the month-year of the first dose of Study Drug, then assign the last 
day of the month. 
• 
after the month-year of the first dose of Study Drug, then assign the first day of the 
month. 
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For end dates: 
Imputation will be performed for the end date only if the day or month is missing (i.e., year is 
present) for a resolved AE as follows: 
• 
If month and day are missing and year is: 
o the same as the year of the last dose of Study Drug, then assign the month-day 
of the last dose of Study Drug  
o otherwise, assign December 31 
• 
If only day is missing, then assign the last day of the month. 
If the imputed start date is later than the imputed end date, then set the imputed start date to the 
imputed end date. 
4.10.2.4 
Adverse Events of Special Interest  
The following AEs are considered AE of special interest for the study. These events will be 
reviewed and evaluated to determine if they meet the criteria.   
• 
Platelet count < 50,000/mm3 accompanied by a major bleeding (MB) event or clinically 
relevant non-major bleeding (CRNMB) event, or platelet count of < 25,000/mm3 
irrespective of a MB or CRNMB event. 
• 
Use of medications (prophylactic treatment such as antihistamines, acetaminophen, 
non-steroidal anti-inflammatory drugs [NSAIDs], corticosteroids, etc.) as pre-treatment to 
avoid a hypersensitivity reaction or recurrence of a previous hypersensitivity reaction. 
Those events will be individually reviewed and evaluated to determine if they meet the criteria. 
The following analyses will be provided. 
• 
The number and percentage of patients experiencing events as well as the total number 
of reported events, risk difference and its 95% CI in the crude incidence rates between 
each active treatment group (or total olezarsen treated) and pooled placebo group, 
classified by PT, will be tabulated by treatment group and total olezarsen treated. 
• 
A cumulative incidence plot if data supported.  
• 
EAIR, risk difference and its 95% CI in EAIRs between each active treatment group (or 
total olezarsen treated) and pooled placebo group, and EAER. classified by PT, will be 
tabulated by treatment group and total olezarsen treated. 
4.10.2.5 
Other Adverse Events of Interest  
The number and percentage of patients experiencing events as well as the number of reported 
events, risk difference and its 95% CI in the crude incidence rates between each active treatment 
group (or total olezarsen treated) and pooled placebo group, classified by PT (unless otherwise 
specified), will be tabulated by treatment group for the following AEs of Interest. 
4.10.2.5.1 
Bleeding TEAEs  
Bleeding TEAEs will be analyzed by SOC and PT for the following categories.  
• 
Bleeding TEAEs (defined based on the ‘Haemorrhages’ Standardized MedDRA Query 
[SMQ, both narrow and broad scope]) 
• 
Clinical bleeding TEAEs, i.e. bleeding TEAEs excluding events at the injection site and 
events related to a laboratory value 
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• 
Clinical bleeding events with concomitant anticoagulant or antiplatelet medication 
• 
Clinical bleeding events without concomitant anticoagulant or antiplatelet medication 
4.10.2.5.2 
Thrombocytopenia TEAE  
Thrombocytopenia TEAE will be analyzed as follows: 
• 
Thrombocytopenia TEAE (defined based on the ‘Thrombocytopenias’ High Level Terms 
[HLT] or ‘Platelet count decreased’ PT) 
4.10.2.5.3 
Hypersensitivity TEAE  
Hypersensitivity TEAEs will be analyzed for the following categories.  
• 
Hypersensitivity TEAE (defined based on the Hypersensitivity SMQ [narrow scope only]) 
by SOC and PT 
• 
TEAEs in the Hypersensitivity FMQ (narrow) by PT. 
• 
Serious TEAEs, fatal TEAEs and TEAEs leading to treatment discontinuation in the 
Hypersensitivity FMQ (narrow) by PT 
• 
Action taken with drug due to TEAEs in the Hypersensitivity FMQ (narrow)  
• 
Rescue medication used in management TEAEs in the Hypersensitivity FMQ (narrow)  
• 
TEAEs in the Hypersensitivity FMQ (broad search, incorporates broad and narrow FMQ 
preferred terms to maximize sensitivity) by PT. 
• 
Serious TEAEs, fatal TEAEs and TEAEs leading to treatment discontinuation in 
Hypersensitivity FMQ (broad search, incorporates broad and narrow FMQ preferred 
terms to maximize sensitivity) by PT 
• 
Action taken with drug due to TEAEs in the Hypersensitivity FMQ (broad search, 
incorporates broad and narrow FMQ preferred terms to maximize sensitivity)  
• 
Rescue medication used in management TEAEs in Hypersensitivity FMQ (broad search, 
incorporates broad and narrow FMQ preferred terms to maximize sensitivity)  
• 
TEAEs in the Hypersensitivity algorithmic FMQ. The FMQ definition is using an 
algorithmic component of the PTs identified within the Hypersensitivity FMQ based on 
the locations that hypersensitivity is known to commonly affect, i.e., airway, skin, soft 
tissue, and systemic.  In addition, the onset of event(s) is within 7 days of the treatment.  
• 
TEAEs in the Anaphylactic reaction FMQ (narrow) by PT 
• 
Serious TEAEs, fatal TEAEs and TEAEs leading to treatment discontinuation in 
Anaphylactic reaction FMQ (narrow) by PT 
For patients who had hypersensitivity reactions, either in FMQ narrow, broad, or algorithmic, the 
time to onset of the first event will be summarized using descriptive statistics.  
For patients who had serious hypersensitivity reactions or discontinued study drug due to 
hypersensitivity reactions, either in FMQ narrow, broad, or algorithmic, a graphical patient profile 
including selected laboratory tests will be provided. 
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4.10.2.5.4 
Renal Impairment TEAE  
Renal impairment TEAEs will be analyzed for the following categories.  
• 
Renal impairment TEAEs (defined based on the ‘Acute renal failure’ SMQ (narrow and 
broad)) by SOC and PT 
• 
TEAEs, serious TEAEs, fatal TEAEs, and TEAEs leading to treatment discontinuation in 
the AKI FMQ (narrow) by PT 
• 
TEAEs, serious TEAEs, fatal TEAEs, and TEAEs leading to treatment discontinuation in 
the AKI FMQ (broad) by PT 
• 
Patients who met the original criteria and revised criteria in the renal monitoring and 
stopping criteria and patients who discontinued study treatment or post treatment 
follow-up due to TEAEs in Acute Kidney Injury (AKI) FMQ (narrow or broad) 
• 
For patients having treatment emergent proteinuria (defined as all events fall under 
proteinuria” SMQ (narrow and broad), the time to onset of the first event will be 
summarized using descriptive statistics 
• 
For patients having treatment emergent albuminuria (defined as all related events fall 
under proteinuria SMQ narrow, including diagnosis tests for albumin/creatinine ratio), the 
time to onset of the first event will be summarized using descriptive statistics 
• 
For patients who had AKI TEAE (FMQ narrow or broad), the time to onset of the first 
event will be summarized using descriptive statistics.  
• 
For patients who had serious AKI TEAE (FMQ narrow or broad), or discontinued study 
drug due to AKI TEAE (FMQ narrow or broad), a graphical patient profile including but 
not limited to eGFR (by CKD-EPI formula 2021), serum creatinine, UACR, UPCR and 
selected electrolytes will be provided. 
• 
For patients who had serious AKI TEAE (FMQ narrow or broad), or discontinued study 
drug due to AKI TEAE (FMQ narrow or broad) or protocol defined renal monitoring or 
stopping criteria (original or revised), a data listing including eGFR (by CKD-EPI formula 
2021), serum creatinine, UACR and UPCR will be provided. 
4.10.2.5.5 
Abnormal Liver Function TEAE  
Abnormal liver function TEAEs will be analyzed for the following categories.  
• 
Abnormal liver function TEAE (defined based on the ‘Drug related hepatic disorders – 
comprehensive search’ SMQ (narrow and broad)) by SOC and PT 
• 
TEAEs, Serious TEAEs, drug-related TEAEs, fatal TEAEs and TEAEs leading to 
treatment discontinuation in Hepatic Injury and Hepatic Failure FMQ (narrow) by PT 
• 
TEAEs in Hepatic Injury and Hepatic Failure FMQ (narrow) by PT 
• 
Patients who discontinued study treatment or post treatment follow-up due to AEs in 
Hepatic Injury or Heptic Failure FDA Medical Query (FMQ) (narrow), Lab abnormality 
(last on treatment ALT ≥ 2 x ULN, AST ≥ 2 x ULN, ALP ≥ 2 x ULN, total 
bilirubin ≥ 1.5 x ULN) for patients in above categories will also be tabulated. 
The number and percentage of patients experiencing events as well as the total number of 
reported events, classified by PT (unless otherwise specified), will be tabulated by treatment 
group for the following AEs of Interest. 
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4.10.2.5.6 
Local Cutaneous Reactions at the Injection Site  
Local cutaneous reaction at injection site (LCRIS) is defined as (A) moderate or severe AEs with 
the preferred terms (PTs) including Injection site erythema, Injection site swelling, Injection site 
pruritus, or Injection site pain that started on the day of injection, persisted for at least 2 days 
(i.e., event onset date on the day of injection and resolution date not on the day of injection or the 
day after injection) or ongoing; or (B) any AE at the Study Drug injection site, regardless of 
severity, that leads to discontinuation of study drug, where AE at the Study Drug injection site is 
the principal reason for discontinuation.  
LCRIS will be summarized by PT for each treatment group and total olezarsen treated. Patients 
with moderate, severe and any LCRIS will also be summarized. Discontinuations due to AE at 
the injection site will be summarized separately. 
Percentage of injections leading to LCRIS will be summarized by PT and overall using the 
descriptive statistics. Additionally, percentage of injections leading to LCRIS will be summarized 
by moderate, severe severity and discontinuation of Study Drug due to AE at injection site. 
Percentage of injections leading to LCRIS will be calculated as follows for each subject: 
(A/B)*100, where A = number of injections with an LCRIS, and B = total number of injections. 
Doses that are split across multiple injections are counted as a single injection.  
The duration to resolution of a LCRIS and the time to onset of the first event will be summarized 
descriptively by treatment group and total olezarsen treated. If there are multiple LCRIS related 
to an injection and no overlap between events, the duration will be calculated as the sum of the 
duration of all LCRIS that are related to the injection. If there are overlaps, the duration will be 
calculated using the earliest start date and latest stop date of all LCRIS that are related to the 
injection. For unresolved LCRIS with missing stop date, the last participation date will be used in 
the calculation.  
In addition, for patients who experienced LCRIS, the number of injections prior to the first LCRIS 
will also be summarized descriptively by treatment group and total olezarsen treated. 
The LCRIS events will be provided in a listing. 
4.10.2.5.7 
Injection Site Reaction  
Injection site reaction (ISR) is defined as any AE with PT or verbatim term containing ‘Injection 
Site’ that persisted for at least 2 days or ongoing. ISR will be summarized by PT for each treatment 
group and total olezarsen treated.  
Percentage of injections leading to ISRs will be summarized by PT and overall using the 
descriptive statistics.  
Percentage of injections leading to ISR will be calculated as follows for each patient: (A/B)*100, 
where A = number of injections with an ISR, and B = total number of injections. Doses that are 
split across multiple injections are counted as a single injection.  
The duration to resolution of an ISR and the time to onset of the first event will be summarized 
descriptively by treatment group and total olezarsen treated. If there are multiple ISRs related to 
an injection and no overlap between ISRs, the duration will be calculated as the sum of the 
duration of all ISRs that are related to the injection. If there are overlaps, the duration will be 
calculated using the earliest start date and latest stop date of all ISRs that are related to the 
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injection. For unresolved ISRs with missing stop date, the last participation date will be used in 
the calculation.  
In addition, for patients who experienced ISR, the number of injections prior to the first ISR will 
also be summarized descriptively by treatment group and olezarsen treated. 
ISR will be listed by preferred term. 
4.10.2.5.8 
Flu-like Reactions  
Flu-like reactions (FLRs) will also be summarized by PT for each treatment group and total 
olezarsen treated.  
Flu-like reactions (FLR) will be evaluated using the following 2 definitions: 
Definition 1 (FLR 1): defined as adverse events with PTs including Influenza like illness, Pyrexia, 
Feeling hot, Body temperature increased, Chills, Myalgia, or Arthralgia, starting on the day of 
injection or next day. 
Definition 2 (FLR 2):  defined as AEs with PTs including either (A) Influenza like illness or 
(B) Pyrexia or Feeling hot or Body temperature increased, plus at least 2 of the following 
symptoms with the PTs: Chills, Myalgia, or Arthralgia, starting on day of injection or the next day.  
Percentage of injections leading to flu-like reactions will be summarized using the descriptive 
statistics.  
Percentage of injections leading to flu-like reactions will be calculated as follows for each subject: 
(A/B)*100, where A = number of injections leading to flu-like reactions, and B = total number of 
injections.  
For the subset of patients experiencing FLR(s), the time to onset of first FLR will be summarized 
using descriptive statistics. 
FLRs will be listed by preferred term. 
4.10.3 Clinical Laboratory Evaluation  
4.10.3.1 
General Analysis of Safety Laboratory Data  
The following is the list of routine lab analytes that will be collected throughout the study: 
• 
Clinical Chemistry: Sodium, Potassium, Chloride, Bicarbonate, Total Protein, Albumin, 
Calcium, Magnesium, Phosphorus, Glucose, Blood Urea Nitrogen (BUN), Creatinine, Uric 
Acid, Total bilirubin, Direct (conjugated) bilirubin, Indirect (unconjugated) bilirubin, Alanine 
aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), 
Creatinine kinase (CK), and Gamma-glutamyl transferase (GGT)  
• 
Hematology: Red blood cells, Hemoglobin, Hematocrit, Mean corpuscular volume 
(MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin 
concentration (MCHC), Red cell distribution width (RDW), Platelets (PLTs), Mean platelet 
volume (MPV), White blood cells (WBCs), and WBC differential (percentage and 
absolute) (Neutrophils, Eosinophils, Basophils, Lymphocytes, and Monocytes) 
• 
Coagulation: activated partial thromboplastin time (aPTT), prothrombin time, 
international normalized ratio (INR)  
• 
Other assessments: Hemoglobin A1C (HbA1c) 
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• 
Screening Tests: Hepatitis B surface antigen, Hepatitis C antibody, HIV antibody, FSH 
(for confirmation of menopause at Screening per inclusion criteria), Serum βhCG (only 
women who are not surgically sterile or post-menopausal). The screening test data will 
only be displayed in patient listings. 
• 
Urinalysis: Color, Appearance, Specific gravity, pH, Protein, Blood, Glucose, Ketones, 
Bilirubin, Urobilinogen, Leukocyte esterase, Nitrate, Microscopic examination, Urinary 
protein/creatinine (UPCR) ratio, Urine albumin/creatinine ratio (UACR). The expanded 
urinalysis data will be only displayed in patient listings. Urine albumin/creatinine ratio 
(a/c ratio) and protein/creatinine ratio (p/c ratio) will be summarized. 
• 
Inflammation: CRP measured by high sensitivity assay (hsCRP) 
If the quantitative data were reported as “< X”, i.e., below the lower limit of quantification, or 
“> X”, i.e., above the upper limit of quantification, will be converted to X for the purpose of 
quantitative summaries/figures, but will be presented as recorded (i.e., “< X” or “> X”) in the 
listings.  
The following clinical laboratory summaries will be provided by treatment group and total 
olezarsen treated. 
• 
Quantitative assessments will be summarized using descriptive statistics in terms of 
observed values, change and percent change from Baseline for each laboratory 
parameter by scheduled study visit.  
• 
Qualitative assessments will be summarized by frequency counts and percentages by 
scheduled study visit. 
By-subject listings of all laboratory data will be provided based on randomized patients. 
4.10.3.2 
Additional Analyses of Key Safety Abnormal Laboratory Data  
The following categories of key safety laboratory data will be evaluated over the whole 
post-baseline period. The number and percent of patients with post-baseline results falling in each 
category below will be tabulated by treatment group and total olezarsen treated. Percentage is 
calculated using the number of subjects with at least one post-baseline result meet the specific 
criteria listed below as numerator and the number of subjects with at least one non-missing 
post-baseline value as denominator. The risk differences and corresponding 95% CIs between 
each active treatment group (total olezarsen treated) and pooled placebo group will be provided 
for the selected categories. Results with visit labels as “Unscheduled” will be included in the 
abnormality summary. 
Liver enzyme elevation 
• 
ALT or AST≥ ULN 
• 
ALT or AST≥ 3 × ULN and ALT or AST ≥ 2 × baseline    
• 
ALT/AST ≥ 3 × ULN, ≥ 5 × ULN, ≥ 8 × ULN, ≥ 10 × ULN, or ≥ 20 x ULN, for patients 
having elevation in liver enzymes (ALT ≥ 3 × ULN), the time to onset of the first event will 
be summarized using descriptive statistics 
• 
Total bilirubin ≥ 2 x ULN, ≥ 5 x ULN, ≥ 8 x ULN 
• 
Direct bilirubin ≥ 2 x ULN, ≥ 5 x ULN  
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• 
Highest post-baseline value of ALT/AST fall in:  ≥ 3 × ULN - < 5 × ULN, ALT ≥ 5 × ULN - 
< 10 × ULN, ALT ≥ 10 × ULN - < 20 × ULN (the risk difference will not be provided for 
this category) 
• 
ALT or AST ≥ 3 x ULN and Total bilirubin ≥ 2 x ULN  
• 
GGT ≥ 2 × ULN 
• 
ALP ≥ 2 × ULN 
• 
ALP ≥ 3× ULN 
• 
ALP ≥ 2 x ULN and (Baseline ALP < 2 x ULN or Baseline ALP missing) 
• 
ALT or AST ≥ 3 x ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was ≥ ULN) and Total bilirubin ≥ 2 x ULN and ALP ≥ 2 x ULN 
• 
ALT/AST ≥ 3 x ULN and INR ≥ 1.5 
• 
INR ≥ 1.5 × ULN 
• 
INR ≥ 3 × ULN 
• 
INR ≥ 5 × ULN 
The number and percent of patients falling in each of the following categories based on confirmed 
post-baseline results will be tabulated by treatment group and total olezarsen treated. A confirmed 
value is based on a consecutive lab value performed on a different day to, but within 10 days of, 
the initial value. If that value is in the same or worse category, then the initial value is confirmed. 
If the consecutive value is in a better category, then the initial value is confirmed using the 
consecutive value category.  If there is no retest within 10 days, then the initial value is presumed 
confirmed.  If there are multiple results on the same day, then the worst value will be utilized in 
the analysis. 
• 
ALT or AST ≥ 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed 
• 
ALT/AST ≥ 3 × ULN, ≥ 5 × ULN, ≥ 10 × ULN, or ≥ 20 x ULN, which is confirmed 
• 
ALT or AST ≥ 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin ≥ 2 × ULN  
• 
ALT or AST ≥ 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin ≥ 2 × ULN and ALP ≥ 2 × ULN 
• 
ALT or AST ≥ 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was ≥ ULN), which is confirmed and INR ≥ 1.5 
For patients having at least 3-fold or greater elevations above the ULN for ALT or AST or for 
patients with baseline ALT or AST ≥ ULN and at least 2-fold increases from Baseline, a listing of 
all of the ALT, AST, total bilirubin, direct bilirubin, GGT, INR, and ALP records for those patients 
will be provided. The confirmed values (i.e., at least 3-fold or greater elevations above the ULN 
for ALT or AST (or the greater of 2 × baseline value or 3 × ULN if the baseline value was ≥ ULN) 
will be flagged. 
Individual spaghetti plots of the ALT, AST, total bilirubin, direct bilirubin, INR, GGT, and ALP for 
those patients having single value at least 3-fold or greater elevations above the ULN for ALT or 
AST or for patients with baseline ALT or AST ≥ ULN and at least 2-fold increases from Baseline 
will be provided in separate files.  
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Additionally, evaluation of Drug Induced Serious Hepatoxicity (eDISH) dot plot where the X-axis 
is the ratio of peak ALT and ULN and the Y-axis is the ratio of peak total bilirubin and ULN will be 
provided by treatment group and total olezarsen treated. The eDISH plot for AST versus total 
bilirubin will also be provided.  
Renal Laboratory Abnormalities 
The number and percent of patients falling in each of the following categories based on results at 
a) any time after first dose) and b) the final visit will be tabulated by treatment group and total 
olezarsen treated:  
• 
Serum creatinine ≥ 0.3 mg/dL higher than baseline  
• 
Serum creatinine ≥ 1.5 × baseline, ≥ 2.0 × baseline, and ≥ 3.0 × baseline 
• 
eGFR (by CKD-EPI formula 2021) decrease from Baseline ≥ 25%, 30%, 50%, 75%, for 
patients having eGFR ≥ 25% decrease from baseline, the time to onset of the first event 
will be summarized using descriptive statistics 
• 
UPCR ≥ 500, 1000, 2000 mg/g  
• 
UACR ≥ 300, 500, 600, 1200 mg/g 
A listing of the creatinine, eGFR (by CKD-EPI formula 2021), UPCR, UACR values over time will 
be provided for each patient with single value meeting any of criteria below. 
Individual spaghetti plots of the Serum Creatinine, UPCR, UACR, eGFR (by CKD-EPI formula 
2021) for patients with single value meet any of criteria below will be provided in separate files.   
• 
eGFR (by CKD-EPI formula 2021) decrease from Baseline ≥ 25% 
• 
UPCR ≥ 500 mg/g Serum creatinine ≥ 1.5 × baseline 
• 
Serum creatinine ≥ 0.3 mg/dL higher than baseline 
Shift table for eGFR (by CKD-EPI formula 2021), UPCR and LDL-C will be provided. The 
categories for the shift table will be: 
• 
eGFR (by CKD-EPI formula 2021): < 30, ≥ 30 and < 60, ≥ 60 mL/min/1.73 m2 
• 
UPCR: < 150 mg/g; 150 to < 500 mg/g; 500 to < 1000 mg/g; ≥ 1000 mg/g 
• 
LDL-C: < 70 mg/dL, 70 to < 100 mg/dL, 100 to < 130 mg/dL, 130 to < 160 mg/dL, 
160 mg/dL to < 190 mg/dL and ≥ 190 mg/dL 
The numbers and percentages of subjects with post-baseline platelets results falling in each of 
the following categories will be summarized for the Safety Set and the subset of patients with 
normal baseline (≥ 140,000/mm3).  
• 
Any single occurrence of platelet count < 140,000/mm3 
• 
Any confirmed platelet count < 140,000/mm3 
• 
Any single occurrence of platelet count < 100,000/mm3, for patients having post-baseline 
platelet count < 100,000/mm3, the time to onset of the first event will be summarized 
using descriptive statistics 
• 
Any confirmed platelet count < 100,000/mm3 
• 
Any single occurrence of platelet count < 75,000/mm3 
• 
Any confirmed platelet count < 75,000/mm3 
• 
Any single occurrence of platelet count < 50,000/mm3 
• 
Any confirmed platelet count < 50,000/mm3 
• 
Any single occurrence of platelet count < 25,000/mm3 
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• 
Any confirmed platelet count < 25,000/mm3 
• 
Worst post-baseline value falling in: 100,000 to < 140,000/mm3, 75,000 to 
< 100,000/mm3, 50,000 to < 75,000/mm3, 25,000 to < 50,000/mm3, 0 to < 25,000/mm3 
(the risk difference will not be provided for this category) 
• 
Confirmed worst post-baseline value falling in: 100,000 to < 140,000/mm3, 75,000 to 
< 100,000/mm3, 50,000 to < 75,000/mm3, 25,000 to < 50,000/mm3, 0 to < 25,000/mm3 
• 
Worst post-baseline platelet reduction from Baseline ≥ 30% and ≥ 50%   
• 
Confirmed worst platelet reduction from Baseline ≥ 30% and ≥ 50%   
• 
Any 2 occurrences of platelet count < 140,000/mm3 on different days 
• 
Any 2 occurrences of platelet count < 140,000/mm3 on different days or any single 
occurrence of platelet count < 100,000/mm3  
Individual spaghetti plots of the Hemoglobin, hematocrit (HCT), WBC, Platelets, aPTT, PT will be 
provided for patients with single or confirmed platelet values < 100,000/mm3 or platelet reduction 
from Baseline ≥ 30% or have any Adverse Event of Special Interest or have any bleeding events. 
Graphs of Mean (±SEM) for key safety lab parameters (i.e., ALT, AST, Total bilirubin, ALP, 
Hemoglobin, hematocrit (HCT), WBC, Platelets, aPTT, INR, PT, Serum Creatinine, UACR, 
UPCR, eGFR (by CKD-EPI formula 2021), HbA1c), change and percent change from Baseline at 
each scheduled visit will be generated.  
The correlation between anti-platelet antibodies and platelet decreases as well as immunogenicity 
(IM) status may be explored if supported by data. 
The following hematology and hepatic enzymes lab results will be categorized based on criteria 
from the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, November 2017 
with modifications specified in APPENDIX D of the protocol and the incidence of shift from 
Baseline to worst post-baseline value taken after the first dose will be summarized. Appendix A 
provides the grading scale summary for these selected analytes based on the guidance above. 
Of note, grade 0 was added to present non-missing lab values that do not meet the criteria for 
any Toxicity Grading Scale. If a patient is missing a baseline value but has a post-baseline value, 
then the baseline assessment will be labelled as “unknown”. Likewise, if a patient has a baseline 
value but has no post-baseline values, then the worst value will be labelled as “unknown”.  
• 
Hemoglobin: shift from Baseline to minimum post-baseline value 
• 
WBCs: shift from Baseline to minimum post-baseline value  
• 
Platelets: shift from Baseline to minimum post-baseline value  
• 
Creatinine: shift from Baseline to maximum post-baseline value   
• 
Total Bilirubin: shift from Baseline to maximum post-baseline value 
• 
ALT: shift from Baseline to maximum post-baseline value   
• 
AST: shift from Baseline to maximum post-baseline value  
• 
Platelets: shift from Baseline to confirmed minimum post-baseline value 
• 
ALT: shift from Baseline to confirmed maximum post-baseline value 
• 
AST: shift from Baseline to confirmed maximum post-baseline value 
Individual data listings of laboratory results will be presented for each subject. All values outside 
the clinical reference ranges will be flagged in the data listings. The abnormal values will be 
flagged with ‘L’ for values below the lower limit of the clinical reference range and ‘H’ for values 
above the upper limit of the clinical reference range and included in the listings. 
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Hypersensitivity Related Analyte Abnormalities 
The number and percentage of patients falling in each abnormality category outlined below will 
be calculated based on the worst post-baseline assessments.   
• 
Eosinophils > 650 cells/µL, > 1500 cells/µL, > 5000 cells/µL 
• 
WBC > 10,800 cells/µL, > 13,000 cells/µL, > 15,000 cells/µL 
4.10.4 Vital Signs and Physical Findings  
4.10.4.1 
Vital Signs  
Vital signs data will include pulse rate (beats/min), respiratory rate (breaths/min), systolic blood 
pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), body temperature (°C), 
weight (kg), height (cm), and body mass index (BMI) (kg/m2). 
Descriptive statistics of observed values, change and percent change from baseline will be 
presented for each vital sign parameter by scheduled study visit. 
Number and percentage of subjects falling in each of the following categories will be tabulated 
by treatment group and total olezarsen treated:  
• 
Maximum change from baseline in SBP > 5, > 10, > 15, > 20, > 30 mmHg  
• 
Maximum change from baseline in DBP > 5, > 10, > 15, > 20, > 30 mmHg  
• 
Maximum change from baseline in pulse rate > 5, > 10, > 15, > 20 beats/min  
A by-subject listing of vital signs data (include change from baseline for weight and BMI), including 
unscheduled visit, will be provided. 
4.10.4.2 
Physical Examinations  
At Screening, any physical examination findings will be recorded on Medical History. At any other 
visit, any worsening or new condition findings will be recorded as an AE. Thus, physical 
examination will be assessed through medical history and AE summaries. A by-subject listing of 
physical examinations will be provided. 
4.10.5 12-Lead Electrocardiograms (ECGs)  
ECGs will be performed at the visits indicated in the protocol Schedule of Procedures.  The ECG 
data will include ventricular rate (VR), PR interval, QRS duration, QT, QTc intervals (machine 
reading), QTc interval calculated using Fridericia’s formula (QTcF) and overall interpretation.   
For the continuous variables above, descriptive statistics of results, the change and percent 
change from baseline to each scheduled study visit, will be presented in summary tables; The 
categorical responses to overall interpretation at each visit will be summarized by counts and 
percentages.   
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The following summary tables will be provided by treatment group and total olezarsen treated:  
• 
A summary of each ECG parameter by visit 
• 
A summary of the number and percentage of subjects with QTcF interval exceeding the 
following predefined upper limits: > 450 msec, > 480 msec, > 500 msec. 
• 
Shift table from baseline to the worst (highest) post-baseline QTcF interval. The 
categories for the shift table will be: ≤ 450 msec, > 450 msec to ≤ 480 msec, > 480 msec 
to ≤ 500 msec, and > 500 msec.   
• 
A summary of the number and percentage of subjects experiencing an increase from 
baseline in QTcF interval of greater than 30 msec or 60 msec at any time post-baseline. 
This analysis will be presented for all subjects in the Safety Set and for the subgroup 
whose QTcF is normal at baseline. Normal QTcF is defined as ≤ 450 msec for males or 
≤ 470 msec for females. Subjects will be counted only once if they had more than one 
such event, so only a subject’s worst post-baseline value will be considered. 
All the ECG data will be listed.  
4.10.6 Data and Safety Monitoring Board (DSMB)  
A DSMB, also known as Data Monitoring Committee, will be assembled to review safety and 
tolerability data collected during this study.  Based on its ongoing assessment of safety and 
tolerability, 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. 
4.11 Other Analyses  
4.11.1 Pharmacokinetics  
PK analysis will include the following, using PK Population: 
• 
Plasma concentrations of olezarsen (measured as total full-length oligonucleotides, 
including fully conjugated, partially conjugated, and unconjugated olezarsen), along with 
the scheduled (nominal) and actual sampling times (i.e., time from Subcutaneous [SC] 
dosing) will be listed (when applicable) for each evaluable patient by cohort, treatment, 
actual dose, gender, patient ID, patient immunogenicity (IM) status, and study day. 
Plasma concentrations below the lower limit of quantification (LLOQ) will be presented 
as “BLQ”. Percent differences between nominal and actual dose, as well as between 
scheduled and actual sampling times will also be listed for all patients. For all patients 
who receive olezarsen treatment, olezarsen  plasma trough (pre-dose) and 
post-treatment concentrations will be summarized using descriptive statistics by cohort, 
treatment, dose, study day, and scheduled time point, with and without stratification by 
subject level ADA data (see Section 4.11.2).  For the purpose of calculating typical 
descriptive statistics (n, mean, SD, %CV, geometric mean, geometric %CV, median, 
minimum and maximum) for plasma concentrations, all below the lower limit of 
quantification (BLQ) values will be set to zero. Mean plasma concentrations that are 
BLQ will be presented as BLQ, and the SD and %CV, as well as geometric mean and 
geometric %CV, will be reported as “NA” (not applicable). At the discretion of the 
pharmacokineticist and/or biostatistician, samples may be excluded from descriptive 
statistics if there are large deviations between scheduled and actual sampling times 
(percentage difference between scheduled and actual sampling time greater than 30%), 
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or large deviations between actual dose and nominal dose (percent difference between 
planned and actual dose greater than 30%). Any samples excluded from the summary 
descriptive statistics, if deemed necessary, will be listed separately along with the 
reason for exclusion. 
• 
For patients who receive olezarsen treatment, the plasma disposition half-life associated 
with the apparent terminal elimination phase will be calculated using a non-compartment 
method, if appropriate, using available data. Other PK parameters, as appropriate, may 
be determined or calculated at the discretion of the PK scientist. Plasma PK parameters 
will be summarized using descriptive statistics (n, mean, SD, %CV, geometric mean, 
geometric %CV, median, minimum, and maximum) by treatment and dose with and 
without stratification by subject level ADA data. 
• 
Population pharmacokinetics and covariate analysis may be performed, combined with 
data from other studies if deemed appropriate, and results, if generated, will be reported 
separately. Exposure-response relationships between selected pharmacokinetic and 
efficacy and safety measures may also be explored, where deemed appropriate. 
4.11.2 Immunogenicity (IM) Analysis  
4.11.2.1 
Sample Level ADA Data  
Samples collected for IM assessment at baseline (Day 1 pre-dose), during treatment and 
post-treatment follow-up period including early termination samples will be analyzed for 
anti-olezarsen antibodies (ADA). 
An evaluable sample will be designated ‘Positive’ based on both positive screening and 
confirmation assay results (i.e., confirmed positive result), and otherwise will be deemed 
‘Negative’. An unevaluable sample, for example, a sample not being stored properly, or 
insufficient volume for analysis, will be reported as “unknown”. Sample ADA results (screen 
positive/negative, confirmed positive/negative or unknown, and when applicable, titer of 
anti-olezarsen antibodies) before, during, and after treatment with study drug (olezarsen or 
placebo) (sample ADA status) will be listed by treatment, dose, and day of collection.   
The sample ADA incidence (number) and incidence rate (percent) at each evaluated study time 
point will be determined and appropriately summarized as the total number of and percentage of 
evaluated subjects with sample ADA negative, positive, and unknown status. Furthermore, titer 
over time will be also appropriately summarized (using descriptive statistics) as median, quartiles 
(25% and 75%), and range by treatment and dose. 
4.11.2.2 
Patient Level ADA Data  
Patient overall ADA status (ADASTAT) will be defined as ‘Positive’ status if they have at least one 
confirmed positive sample result at any time during the treatment or post-treatment evaluation 
periods; ‘Negative’ status if all evaluated ADA sample results during the treatment and 
post-treatment evaluation periods are ADA negative and they have at least one evaluable ADA 
result collected post study drug treatment. Otherwise, patient overall ADA status will be assigned 
‘Unknown’.   
Furthermore, patients with positive overall ADA status may be further classified into different ADA 
types (ADATYPE) based on their baseline ADA status and change in ADA titer post-treatment as 
described below (Shankar et al., 2014): 
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• 
Treatment-Emergent ADA: subjects with either treatment-induced ADA or treatment-
boosted ADA as described below: 
o Treatment-Induced ADA: ADA developed de novo (seroconversion) following study drug 
administration (i.e., formation of ADA any time after the initial drug administration in a 
subject without pre-existing ADA, i.e., baseline negative ADA) 
o Treatment-Boosted ADA: pre-existing ADA that were boosted to a higher level following 
study drug administration (i.e., any time after the initial drug administration the ADA titer 
is greater than the baseline titer by a factor of 8-fold or more 
• 
Treatment-Unaffected ADA: pre-existing ADA that were not affected (boosted) following 
biologic drug administration (i.e., any time after the initial drug administration the ADA 
titer is 4-fold or less) 
• 
For patients with negative overall ADA status, ADATYPE would be classified as baseline 
negative or baseline positive, based on their baseline ADA status. 
Other patient level IM parameters to be calculated/defined may include but not limited to: 
• 
ADA category (ADACAT) will include subjects with Negative, Treatment-Unaffected, and 
Treatment-Emergent ADA status as described above. 
• 
Patient ADA Status at Baseline (ADASTATB): "Positive" if the subject has Week 1 Day 1 
pre-dose sample (baseline) tested as confirmed positive; "Negative" if the patient has 
Week 1 Day 1 pre-dose sample (baseline) tested as confirmed negative; "Unknown" if 
the patient has Week 1 Day 1 pre-dose sample (baseline) unevaluable. 
• 
First day of ADA detected (TFSTADA): i.e., the first day positive ADA sample was 
observed, will be calculated by: the date of first sample has “positive” sample IM status - 
first dose date +1. 
• 
Onset of treatment-emergent ADA (ONSETTE): i.e., the first day treatment-emergent 
ADA (treatment-induced or treatment-boosted ADA) was observed, will be calculated by: 
o  For treatment-induced ADA: the date of first sample has “positive” sample IM 
status - first dose date +1 
o For treatment-boosted ADA: the date of the first sample has ADA titer greater 
than the baseline titer by a factor of 8-fold or more – first dose date +1 
• 
Last Positive ADA Study Day (TLSTADA): defined as the last positive ADA sample 
observed from the start of study drug treatment and will be calculated by: the date of last 
sample has “positive” sample IM status - first dose date +1 
• 
Last IM Sampling Study Day (TLSTSAMP): defined as the last ADA sample collected 
from the start of study drug treatment and will be calculated by: the date of last sample 
collected - first dose date +1 
• 
Duration of treatment-emergent ADA (DURTE): i.e., the total duration of treatment 
emergent ADA during the study, and will be calculated using the last sample result 
carried forward. This parameter will be calculated for patients with treatment-induced 
ADA and treatment boosted ADA. 
• 
Peak titer (PEAKTIT): the highest titer observed for the patient  
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• 
Time to peak titer (TPEAKTIT): the time to reach peak titer will be calculated by: the date 
of first peak titer observed- first dose date +1 
• 
Total number of ADA Positive Samples (NOPOSAMP): the total number of ADA samples 
being confirmed positive for the patient  
• 
Total number of ADA Samples evaluated (NOADASAMT): the total number of ADA 
samples being collected and analyzed successfully with reportable results for the patient 
Lastly, patients with positive ADA status may further be classified as being transient or 
persistent ADA response, if there are sufficient number of patients with transient ADA status. 
Transient and persistent ADA definitions are defined below and based on Shankar et al., 2014: 
• 
Transient ADA response:  
o Treatment-induced ADA detected only at one sampling time point during the 
treatment or follow-up observation period (excluding the last sampling time point, 
which will be considered persistent unless shown to be undetectable at a later time) 
or 
o Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the ﬁrst and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the subject’s last sampling time point is ADA-negative. 
• 
Persistent ADA response: 
o Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the ﬁrst and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
of 16 weeks or longer or 
o Treatment-induced ADA detected only at the last sampling time point of the study 
treatment period or at a sampling time point with less than 16 weeks before an 
ADA-negative last sample. 
The patient level ADA prevalence, incidence, and positive ADA response being transient or 
persistent (if applicable) will be calculated as the total number of and percentage of evaluated 
patients with IM negative, positive, and unknown status by treatment and dose. Patient level IM 
parameters (as described above), if applicable, will be listed for by treatment and dose for all 
evaluable patients, and also appropriately summarized (using descriptive statistics) as median, 
quartiles (25% and 75%) and range by treatment and dose. 
4.11.2.3 
Evaluation of IM Impact on Selected PK, PD, Efficacy, and Safety Measures  
• 
The impact of IM on selected PK, PD, efficacy, and safety measures will be evaluated by 
stratifying plasma PK exposure measures (such as plasma trough and post-treatment 
olezarsen concentrations, etc.), selected PD, clinical efficacy endpoints and safety 
measures by patient level ADA data, summarized using typical descriptive statistics, and 
presented graphically and/or in tables. Efficacy measures to be stratified by patient level 
ADA data will include but may not be limited to apoC-III and TG levels. Safety measures 
to be stratified by patient level ADA data will include but may not be limited to AEs, and 
lab tests for hematology, liver and kidney functions, as appropriate.   
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Lastly, other stratifications (e.g., based on antibody titer, onset of ADA, patient ADA status at 
baseline, etc.) of selected PK, efficacy and safety assessments may also be performed if deemed 
warranted at the discretion of the pharmacokineticist, medical monitor, and/or biostatistician. 
4.11.3 Additional/Exploratory Analyses  
4.11.3.1 
The Adjudicated MACE Incidence Rates  
The adjudicated MACE incidence rates (number and percent of subjects), exposure adjusted 
incidence (EAIR) and event rates (EAER) will be summarized by treatment group and total 
olezarsen treated. Additional analyses of MACE composite of CV death, non-fatal MI, non-fatal 
ischemic stroke, or arterial revascularization (coronary or non-coronary), and the triple composite 
of CV death, non-fatal MI, or non-fatal ischemic stroke may be performed depending on rates of 
MACE. The event rate will be calculated as number of adjudicated treatment emergent MACEs 
divided by the total duration of follow-up time. 
4.11.3.2 
Summary of Lipid Parameters  
All lipid data including results, absolute changes and percent changes from Baseline will be 
summarized using descriptive statistics by treatment group, total olezarsen treated and study visit. 
The means plus/minus SEMs for results, absolute changes and percent changes will be plotted 
over time by treatment group. 
4.11.3.3 
Response Rates  
The response rates based on various TG threshold (fasting TG < 135 mg/dL; < 150 mg/dL; > 2000 
mg/dL in subgroup of patients with baseline fasting TG ≤ 2000 mg/dL) and TG percent reductions 
(≥ 40%, ≥ 50%, ≥ 60%, ≥ 70% reduction) at Month 6 and Month 12 will be compared between 
each olezarsen treatment group and pooled placebo group using a logistic regression model with 
the treatment group and natural log transformed baseline fasting TG as a covariate. Missing TG 
values will be imputed using the same multiple imputation method as the primary analysis of the 
primary endpoint. 
4.12 Determination of Sample Size  
With 33 patients in each olezarsen treatment group and 22 in the placebo group, there would be 
an approximately 80% power to detect a 60% difference between each olezarsen treatment group 
and placebo group at an alpha level of 0.05 (two-sided), assuming 60% reduction in the olezarsen 
treatment patients, no change in the placebo patients, and a common SD of approximately 73%.  
Approximately 152 patients will be enrolled in this trial to account for potential early dropouts. 
4.13 Changes to Protocol-planned Analyses  
In protocol, it states: ’All primary and secondary endpoints will be assessed on the FAS and PPS, 
with the former being the basis for the primary efficacy analysis.’ The secondary endpoints on 
PPS will not be assessed in this SAP. 
In protocol, it states: The missing TG value at Months 6 or 12 will be imputed using an imputation 
model that contains the following variables: baseline fasting TG, fasting TG at each post-baseline 
visits and the multiple imputation will be stratified by treatment group (Schafer 1997; Schafer 
1999). The missing value imputation method for the primary analysis is updated in the SAP as 
below:  
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The retrieved dropouts multiple imputation approach will be used for imputing missing values after 
discontinuation for the primary efficacy analysis. If there is not a sufficient number of retrieved 
dropouts, a placebo washout multiple imputation approach will be used for imputing missing 
values for the primary efficacy analysis. 
5 REFERENCES  
Banks, PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis--2012: revision of 
the Atlanta classification and definitions by international consensus. Gut 2013; 62: 102-111.  
Carpenter J, Roger J, and Kenward M. Analysis of longitudinal trials with protocol deviations: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. Journal 
of Biopharmaceutical Statistics 2013; 23: 1352-1371. 
Hicks, KA, Mahaffey KW, Mehran R, et al. 2017 Cardiovascular and Stroke Endpoint Definitions 
for Clinical Trials. Circulation 2018; 137: 961-972.  
Little RJA and Rubin DB. Statistical analysis with missing data. Second Edition, New York: John 
Wiley & Sons 2002. 
SAS® Version 9.4 of the SAS System for Personal Computers. Copyright ©2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
Schafer JL. Analysis of incomplete multivariate data. New York: Chapman and Hall 1997. 
Schafer JL. Multiple imputation: A Primer. Statistical Methods in Medical Research 1999;8: 3 
Shankar, G., Arkin, S., Cocea, L., Devanarayan, V., Kirshner, S., Kromminga, A., Quarmby, V., 
Richards, S., Schneider, C.K., Subramanyam, M., Swanson, S. (2014). Assessment and 
reporting of the clinical immunogenicity of therapeutic proteins and peptides—harmonized 
terminology and tactical recommendations. The AAPS journal, 16(4), 658-673. 
Thygesen, K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction 
(2018). J Am Coll Cardiol 2018; 72: 2231-2264. 
 
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6 APPENDICES  
6.1 
Appendix A – Grading Scale for Selected Lab Analytes with Abnormal Values  
Parameter 
Unit 
Mild  
Moderate 
Severe  
Hemoglobin 
Decreased 
(Anemia) 
g/dL 
< LLN - 10.0 
< 10.0–8.0 
< 8.0  
WBC 
Decreased 
cell/mm
3 
< LLN - 3,000 
< 3,000–2,000 
< 2,000 
Platelets 
Decreased 
cell/mm
3 
< LLN - 75,000 
< 75,000–50,000 
< 50,000 
Creatinine 
Increased 
 
> ULN-1.5 × ULN if 
baseline normal 
> 1.0–1.5 × baseline if 
baseline abnormal 
> 1.5–3.0 × ULN if 
baseline normal 
> 1.5–3.0 × baseline if 
baseline abnormal 
> 3.0 × ULN if baseline 
normal 
> 3.0 × baseline if 
baseline abnormal 
ALT, AST 
Increased  
 
> ULN-3.0 × ULN if 
baseline normal 
> 1.5–3.0 × baseline if 
baseline abnormal 
> 3.0–5.0 × ULN if 
baseline normal 
> 3.0–5.0 × baseline if 
baseline abnormal 
> 5.0 × ULN if baseline 
normal 
> 5.0 × baseline if 
baseline abnormal 
Total 
Bilirubin 
Increased 
 
> ULN-1.5 × ULN if 
baseline normal 
> 1.0–1.5 × baseline if 
baseline abnormal 
> 1.5–3.0 × ULN if 
baseline normal 
> 1.5–3.0 × baseline if 
baseline abnormal 
> 3.0 × ULN if baseline 
normal 
> 3.0 × baseline if 
baseline abnormal 
 
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