Conditions: Familial Chylomicronemia Syndrome
Keywords: FCS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate the efficacy of olezarsen as compared to placebo on the percent change in fasting triglycerides (TG) from baseline.

Detailed description:
This was a multi-center, double-blind, Phase 3 study in up to 60 patients with FCS. Participants were randomized in a 2:1 ratio to receive Olezarsen or matching placebo in a 53-week treatment period. The length of participation in the study was approximately 74 weeks, which included an up to 8-week screening period, a 53-week treatment period, and a 13-week post-treatment evaluation period. Following the treatment period, eligible patients had the option to enroll in the Open-label Extension (OLE) Study ISIS 678354-CS13 (NCT05130450).

Arms:
arm 1: Participants received olezarsen-matching placebo, once every 4 weeks by subcutaneous (SC) injection, during Weeks 1 to 49 of the 53-week treatment period. arm 2: Participants received olezarsen, 50 milligrams (mg), once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period. arm 3: Participants received olezarsen 80 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

Interventions: intervention 1: Olezarsen intervention 2: Placebo
Intervention descriptions: intervention 1: Olezarsen was administered by SC injection. intervention 2: Olezarsen-matching placebo was administered by SC injection.

Protocol document:
Prot_SAP_000.pdf: 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AKCEA‑APOCIII‑LRx 
Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS) 
 
NCT04568434 
 
02 Aug 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ionis.com 


                    ISIS 678354-CS3                                                                                                                    Ionis Pharmaceuticals, Inc. 
Page 1 of 7 
 
Summary of Clinical Study Results 
A Study of Olezarsen Administered to Patients With Familial 
Chylomicronemia Syndrome (FCS) (Balance) 
Protocol #: ISIS 678354-CS3 
Study dates: November 2020 to October 2023  
Thank you to the participants who took part in the study, “A Study of Olezarsen 
(Formerly Known as AKCEA-APOCIII-LRx) Administered to Patients With Familial 
Chylomicronemia Syndrome (FCS),” also known as the Balance study. 
This study helped researchers find out if a drug called olezarsen could lower fat 
particles in blood (triglyceride levels) in participants who live with familial 
chylomicronemia syndrome (FCS). 
 
Why was this study done? 
FCS is a rare genetic disease. Genes are small pieces of DNA that provide instructions 
to the body to make proteins. Genetic diseases are passed on from parents to children 
through altered (mutated) genes.  
 
FCS is characterized by the buildup of fat particles (triglycerides) in the blood that can 
result in severe abdominal pain and other serious health problems. FCS is caused by 
mutated genes that affect a special protein called lipoprotein lipase (LPL). LPL helps 
break down triglycerides, which are stored in round particles made of protein and fat 
called lipoproteins. The body uses lipoproteins to transport fat after consuming food. 
In people with FCS, LPL is missing or does not work well, and the body is unable to 
break down triglycerides and process fat. This causes the body to have high levels of 
lipoproteins containing fats, which means people with FCS must continuously adhere 
to an extremely strict low-fat diet. 
 
People with FCS have 10 to 100 times the normal amount of triglycerides in their blood. 
Symptoms of FCS include nausea, vomiting, brain fog, belly pain, and the appearance 
of small, yellowish bumps on the skin filled with fat. People with FCS are at a high risk 
of developing a severe condition called pancreatitis, which is the inflammation of the 
pancreas due to high levels of triglycerides in the blood and can be life-threatening.  
 
The most common treatments for FCS include a very low-fat diet and avoiding any 
alcohol intake. However, these steps are difficult to achieve for most people. 
Researchers are looking for medicines that can help lower the triglycerides in the 
blood and reduce the risk of inflammation of the pancreas. 
   


                    ISIS 678354-CS3                                                                                                                    Ionis Pharmaceuticals, Inc. 
Page 2 of 7 
 
In this study, researchers looked at a potential new medication called olezarsen. This 
drug is designed to reduce the actions of a protein called apoC-III, which regulates 
triglyceride levels in the blood. By lowering levels of apoC-III, researchers expect 
olezarsen to help lower triglyceride levels. Researchers studied the effects of 
olezarsen administered to participants with FCS compared with the effects of 
placebo. A placebo is an inactive substance that looks like and is administered as the 
study medication but does not actually contain any medicine. 
Researchers wanted to learn more about the effect of olezarsen on triglyceride levels 
and what side effects it may cause. Researchers also wanted to learn if treatment with 
olezarsen reduced the occurrence of pancreatitis events. 
 
When was this study done? 
This study started in November 2020 and ended in October 2023. 
 
Who took part in this study? 
Participants could take part if: 
• At least 18 years old 
• Had FCS  
• During screening (determining eligibility), had a triglyceride level of at least 880 
milligrams per deciliter (mg/dL) after fasting (not eating). A milligram is one-
thousandth of a gram. A gram is about 1/30 of an ounce. A deciliter measure 
fluid volume that is 1/10 liter. A liter is a little bigger than a quart. 
Participants could not take part if they: 
• Had acute coronary syndrome, or conditions that reduced or stopped blood flow 
to the heart, within 6 months of starting the study 
• Had major surgery within 3 months of starting the study 
• Had other conditions that the researchers believed would interfere with the 
study 
For more information on who could take part in this study, please refer to the websites 
listed at the end of this summary. 
 
How many people took part in this study? 
Altogether, 66 participants took part in this study, of whom 28 were men (42%) and 38 
were women (58%). Participants were between 18 and 78 years of age.  
The study took place at 29 clinics in Canada, France, Italy, Netherlands, Norway, 
Portugal, Slovakia, Spain, Sweden, the United Kingdom, and the United States.  
• 29 participants (44%) enrolled in North America 
• 37 participants (56%) enrolled in Europe 


                    ISIS 678354-CS3                                                                                                                    Ionis Pharmaceuticals, Inc. 
Page 3 of 7 
 
What happened during the study? 
What did researchers want to know? 
Researchers wanted to know how well olezarsen worked to lower triglyceride levels in 
the blood of participants with FCS.  
The main question researchers wanted to answer was: 
How did triglyceride levels change after 6 months of treatment in participants 
who took olezarsen compared with those who took placebo?  
To address this question, researchers took blood samples and compared triglyceride 
levels at the start of the study to triglyceride levels after 6 months of treatment with 
olezarsen.  
Participants had to fast for at least 10 hours before each blood sample was taken. 
What treatments were studied? 
• Olezarsen, 50 or 80 milligrams (mg), given as an injection under the skin 
(subcutaneous). 
• Placebo, given as an injection under the skin. Both olezarsen and placebo were 
injected once every 4 weeks.  
How was the study done? 
There are many types of clinical studies. This study was: 
• Phase 3: This is usually the last phase of clinical study before a new drug is 
submitted to government authorities for approval. A study at this phase is used 
to confirm the effect of a drug and learn more about how safe and tolerable it is. 
• Randomized: Who got which dose of olezarsen or placebo was decided 
randomly by a computer program. 
• Placebo-controlled: Researchers used a placebo to learn the effect of 
olezarsen.  
• Double-Blind: Neither researchers nor participants knew who was getting 
olezarsen or placebo. 
Before the study began, all participants were screened (evaluated) to be sure they 
were a good fit for the study.  
Screening Period 
• During the screening, participants were placed on a stable low-fat diet during 
the first 2 weeks. This diet would continue through the rest of the study. 
• The screening included laboratory tests, physical tests, and genetic tests for 
FCS. The participants were also asked to answer a set of questions 
(questionnaires) to check their disease state and quality of life.  
• The screening lasted for 4 to 8 weeks. 


                    ISIS 678354-CS3                                                                                                                    Ionis Pharmaceuticals, Inc. 
Page 4 of 7 
 
Treatment Period 
• Following the screening period, participants were placed into 1 of 2 groups.  
• Group 1 received either 50 mg olezarsen or a matching placebo once every 4 
weeks. Group 2 received 80 mg olezarsen or a matching placebo also once 
every 4 weeks. 
o Group 1 had 22 participants receiving olezarsen 80 mg 
o Group 2 had 21 participants receiving olezarsen 50 mg 
o Groups 1 and 2 had a total of 23 participant receiving placebo 
• During the treatment, blood samples were collected every 4 weeks to check for 
the levels of triglycerides in the blood. 
• Participants also completed questionnaires to check their own state and 
symptoms of the disease. They recorded any medical problems they had 
during the treatment.  
• The treatment period lasted for 52 weeks (1 year).  
Follow-up Period 
• After ending their treatment, participants entered a 13-week follow-up period or 
an extension study if they completed the entire year of treatment. 
• The extension study allowed researchers to collect more information on the 
safety and effectiveness of olezarsen.  
• Those participants who did not move onto the extension study were followed up 
every 4 weeks of the 13-week follow-up period to check the safety and 
effectiveness of olezarsen. 
Participants had check-up visits at the study clinic, both during treatment and for up to 
13 weeks after treatment. Researchers observed participants’ health and checked for 
any side effects. 
 
What were the results of the study? 
The results below include all 66 participants who received at least 1 dose of olezarsen 
or placebo. 
How did the triglyceride levels change after 6 months of treatment in participants 
who took olezarsen compared to those who took placebo? 
Researchers wanted to compare the change in fasted triglyceride levels from the start 
of the study between the olezarsen and placebo groups.  
After 6 months:  
• The triglyceride levels in the participants who received 80 mg of olezarsen 
decreased by 44% compared with placebo.  
• The triglyceride levels in the participants who received 50 mg of olezarsen 
decreased by 22% compared with placebo. 


                    ISIS 678354-CS3                                                                                                                    Ionis Pharmaceuticals, Inc. 
Page 5 of 7 
 
Researchers considered the change in the participants who received 80 mg of 
olezarsen to be meaningful. Results in the group of participants that received 80 mg of 
olezarsen every 4 weeks had a reduction in triglyceride levels that were statistically 
significant from placebo. Statistical significance means that the numbers are reliably 
different, greatly aiding in data analysis. The participants who received 50 mg of 
olezarsen every 4 weeks had a reduction in triglyceride levels, but compared with 
placebo, was not statistically significant. 
How did the occurrence of pancreatitis change after 1 year of treatment in 
participants who took olezarsen compared to those who took placebo? 
Researchers wanted to compare the occrence of pancreatitis from the start of the study 
between the olezarsen and placebo groups. 
After 1 year there was an 88% decrease in occurence of pancreatitis in participants 
that received olezarsen compared with placebo. Researchers considered this change 
to be meaningful. 
For more information on the study results, refer to the websites listed at the end of this 
summary. 
 
What drug-related side effects did participants have during the 
study? 
A summary of the drug-related side effects that happened during the study is shown 
below. Not all participants had side effects. The results include all participants who 
received at least 1 dose of olezarsen or placebo.  
Side effects are unwanted medical problems thought to be caused by a medicine or a 
medical treatment.  
A side effect is called serious when it results in death, is life-threatening, causes lasting 
problems, or requires hospital care. 
• Total participants: 66 
• 13 out of 43 participants (30%) who received olezarsen had side effects. 
o Olezarsen 50 mg group: 6 out of 21 participants (29%) had side effects 
o Olezarsen 80 mg group: 7 out of 22 participants (32%) had side effects 
• 5 out of 23 participants (22%) who received placebo had side effects 
• No participants in any group had serious side effects. 
• 2 out of 43 participants (5%) who received olezarsen stopped treatment due to 
side effects. 
o Olezarsen 50 mg group: 0 participants stopped treatment 
o Olezarsen 80 mg group: 2 out of 22 participants (9%) stopped treatment 
o Placebo group: 0 participants stopped treatment 
• No participants died due to side effects. 


                    ISIS 678354-CS3                                                                                                                    Ionis Pharmaceuticals, Inc. 
Page 6 of 7 
 
The most common side effects that were reported in at least 15% of participants were: 
• Corona Virus (COVID19) 
o 6 out of 21 participants (29%) who received olezarsen 50 mg 
o 3 out of 22 participants (14%) who received olezarsen 80 mg 
o 8 out of 23 participants (35%) who received placebo  
• Abdominal Pain 
o 3 out of 21 participants (14%) who received olezarsen 50 mg 
o 4 out of 22 participants (18%) who received olezarsen 80 mg 
o  8 out of 23 participants (35%) who received placebo  
• Diarrhea 
o 1 out of 21 participants (5%) who received olezarsen 50 mg 
o 2 out of 22 participants (9%) who received olezarsen 80 mg 
o  6 out of 23 participants (26%) who received placebo  
• Headache 
o 4 out of 21 participants (19%) who received olezarsen 50 mg 
o 1 out of 22 participants (5%) who received olezarsen 80 mg  
o 3 out of 23 participants (13%) who received placebo  
• Pancreatitis 
o 2 out of 21 participants (10%) who received olezarsen 50 mg 
o 1 out of 22 participants (5%) who received olezarsen 80 mg 
o 4 out of 23 participants (17%) who received placebo   
• Fatigue 
o 1 out of 21 participants (5%) who received olezarsen 50 mg 
o 1 out of 22 participants (5%) who received olezarsen 80 mg 
o  4 out of 23 participants (17%) who received placebo   
 
How has this study helped patients and researchers? 
Researchers look at the results of many studies to decide which medicines work and 
are safest for participants. This summary gives the results of 66 participants in a single 
study. Other studies may have more participants and may give different results. 
Overall, researchers learned that olezarsen 80 mg led to a meaningful reduction in the 
levels of triglycerides in the blood after treatment. Researchers also found no new 
serious safety concerns with olezarsen. 
Findings from this study may be used in other studies to learn more about the use of 
olezarsen in participants with FCS. 
 


                    ISIS 678354-CS3                                                                                                                    Ionis Pharmaceuticals, Inc. 
Page 7 of 7 
 
Are there plans for further studies? 
Further clinical studies with olezarsen are ongoing at this time. 
 
Where can I find out more about this study? 
• Official Title of this Study: A Randomized, Double-Blind, Placebo-Controlled, 
Phase 3 Study of AKCEA‑APOCIII‑LRx Administered Subcutaneously to 
Patients with Familial Chylomicronemia Syndrome (FCS) 
• Protocol Number: ISIS 678354-CS3  
• EU Study Number: 2020-002536-67 
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002536-67 
• US Study Number: NCT04568434 
https://www.clinicaltrials.gov/study/NCT04568434 
• New England Journal of Medicine Publication 
Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, et al. Olezarsen, Acute 
Pancreatitis, and Familial Chylomicronemia Syndrome. The New England Journal of 
Medicine. 2024. 
 




ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
2 
ISIS 678354-CS3 
Amendment 9 
EudraCT No:  2020-002536-67  
Clinical Phase:  3 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of 
AKCEA‑APOCIII‑LRX Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
 
Protocol History: 
Original Protocol: 
21 May 2020 
Amendment 1: 
7 August 2020 
Amendment 2: 
30 October 2020 
Amendment 3: 
22 December 2020 
Amendment 4: 
12 March 2021 
Amendment 5: 
16 April 2021 
Amendment 6: 
25 October 2021 
Amendment 7: 
26 October 2022 
Amendment 8: 
19 June 2023 
 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA 92010 
 
See electronic signature and date attached at end of document 
 
Clinical Development 
 
 
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc and Akcea Therapeutics, Inc. that 
must not be disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information cannot be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of Ionis 
Pharmaceuticals, Inc. and Akcea Therapeutics, Inc. 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
3 
Protocol Signature Page 
 
Protocol Number: 
ISIS 678354-CS3 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of 
AKCEA‑APOCIII‑LRX Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
Amendment:  
Amendment 9 
Date:  
 
2 August 2023 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled 
“A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AKCEA‑APOCIII‑LRX 
Administered Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS)” 
dated 2 August 2023, 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. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.  
 
 
 
 
 
Investigator’s Signature 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT .......................................................................................................10 
PROTOCOL SYNOPSIS ..............................................................................................................11 
STUDY DESIGN AND TREATMENT SCHEMA ......................................................................18 
STUDY GLOSSARY ....................................................................................................................19 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................21 
1.1. 
Objectives ...................................................................................................................21 
1.1.1. 
Primary Objective .......................................................................................................21 
1.1.2. 
Secondary Objectives .................................................................................................21 
1.1.3. 
Additional/Exploratory Objectives .............................................................................21 
1.2. 
Study Endpoints ..........................................................................................................21 
1.2.1. 
Primary Endpoint ........................................................................................................21 
1.2.2. 
Secondary Endpoints ..................................................................................................22 
1.2.3. 
Additional/Exploratory Endpoints ..............................................................................23 
1.2.4. 
Safety Endpoints .........................................................................................................23 
2. 
BACKGROUND AND RATIONALE .......................................................................23 
2.1. 
Overview of Disease ...................................................................................................23 
2.2. 
Therapeutic Rationale .................................................................................................24 
2.3. 
ISIS 678354 ................................................................................................................26 
2.3.1. 
Mechanism of Action .................................................................................................26 
2.3.2. 
Chemistry ....................................................................................................................27 
2.3.3. 
Preclinical Experience ................................................................................................28 
2.3.4. 
Clinical Experience .....................................................................................................29 
2.4. 
Rationale for Dose and Schedule of Administration ..................................................32 
2.5. 
Benefit-Risk Assessment ............................................................................................33 
2.5.1. 
Overall Assessment of Benefit:Risk ...........................................................................33 
2.5.2. 
Additional Risks During the COVID-19 Pandemic ...................................................33 
3. 
EXPERIMENTAL PLAN ..........................................................................................34 
3.1. 
Study Design ...............................................................................................................34 
3.2. 
Number of Study Centers ...........................................................................................34 
3.3. 
Number of Patients .....................................................................................................34 
3.4. 
Overall Study Duration and Follow-up ......................................................................35 


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3.4.1. 
Screening ....................................................................................................................35 
3.4.2. 
Treatment Period ........................................................................................................35 
3.4.3. 
Post-Treatment Period ................................................................................................35 
3.5. 
End-of-Study ...............................................................................................................35 
3.6. 
Data and Safety Monitoring Board or Independent Data Monitoring 
Committee ...................................................................................................................35 
3.7. 
Allowances in the Circumstance of a Public Health Emergency ...............................36 
4. 
PATIENT ENROLLMENT ........................................................................................37 
4.1. 
Screening ....................................................................................................................37 
4.2. 
Randomization ............................................................................................................37 
4.3. 
Replacement of Patients .............................................................................................38 
4.4. 
Unblinding of Treatment Assignment ........................................................................38 
5. 
PATIENT ELIGIBILITY ...........................................................................................38 
5.1. 
Inclusion Criteria ........................................................................................................38 
5.2. 
Exclusion Criteria .......................................................................................................40 
6. 
STUDY PROCEDURES ............................................................................................41 
6.1. 
Study Schedule ...........................................................................................................41 
6.1.1. 
Screening ....................................................................................................................41 
6.1.2. 
Treatment Period ........................................................................................................42 
6.1.3. 
Post-Treatment Period ................................................................................................42 
6.2. 
Additional Study Assessments ...................................................................................42 
6.2.1. 
Laboratory Assessments .............................................................................................42 
6.2.2. 
Physical Exams and Vital Signs .................................................................................44 
6.2.3. 
Electrocardiography ....................................................................................................44 
6.2.4. 
Pharmacokinetic Sampling .........................................................................................44 
6.2.5. 
Patient Reported Outcomes Assessments ...................................................................44 
6.2.6. 
Pancreatitis Medical History .......................................................................................44 
6.3. 
Restriction on the Lifestyle of Patients .......................................................................45 
6.3.1. 
Prevention of Pregnancy .............................................................................................45 
6.3.2. 
Other Requirements ....................................................................................................46 
7. 
STUDY DRUG ...........................................................................................................46 
7.1. 
ISIS 678354 or Placebo ..............................................................................................46 
7.2. 
Packaging and Labeling ..............................................................................................46 


ISIS 678354-CS3 
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7.3. 
Study Drug Accountability .........................................................................................47 
8. 
TREATMENT OF PATIENTS ..................................................................................47 
8.1. 
Study Drug Administration.........................................................................................47 
8.2. 
Other Protocol-Required Drugs ..................................................................................47 
8.3. 
Other Protocol-Required Treatment Procedures ........................................................47 
8.4. 
Treatment Precautions ................................................................................................47 
8.5. 
Safety Monitoring Rules .............................................................................................47 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ..................................................48 
8.5.2. 
Safety Monitoring for Renal Function ........................................................................49 
8.5.3. 
Safety Monitoring for Platelet Count Results .............................................................50 
8.5.4. 
Safety Monitoring for Bleeding Events ......................................................................52 
8.5.5. 
Safety Monitoring for Constitutional Symptoms .......................................................53 
8.5.6. 
Safety Monitoring for Potential Hypersensitivity Reactions ......................................53 
8.5.7. 
Safety Monitoring for LDL-C Elevations ...................................................................54 
8.6. 
Stopping Rules ............................................................................................................54 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations .........................................................54 
8.6.2. 
Stopping Rules for Renal Function Test Results ........................................................55 
8.6.3. 
Stopping Rule for Platelet Count Results ...................................................................56 
8.6.4. 
Stopping Rule for Bleeding Events ............................................................................56 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................56 
8.8. 
Discontinuation of Study Drug ...................................................................................56 
8.8.1. 
Follow-up Visits for Early Termination from Treatment Period or 
Post-Treatment Follow-up Period ...............................................................................56 
8.9. 
Withdrawal of Patients from the Study Procedures ....................................................57 
8.10. 
Concomitant Therapy and Procedures ........................................................................57 
8.10.1. 
Concomitant Therapy .................................................................................................58 
8.10.2. 
Concomitant Procedures .............................................................................................58 
8.11. 
Treatment Compliance ................................................................................................58 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................58 
9.1. 
Sponsor Review of Safety Information ......................................................................58 
9.2. 
Regulatory Requirements ...........................................................................................59 
9.3. 
Definitions ..................................................................................................................60 
9.3.1. 
Adverse Event .............................................................................................................60 


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9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction ............60 
9.3.3. 
Serious Adverse Event ................................................................................................61 
9.3.4. 
Adverse Event of Special Interest ...............................................................................61 
9.4. 
Monitoring and Recording Adverse Events ...............................................................62 
9.4.1. 
Serious Adverse Events ..............................................................................................62 
9.4.2. 
Non-Serious Adverse Events ......................................................................................62 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) .........................................62 
9.4.3.1. 
Relationship to the Study Drug...................................................................................63 
9.4.3.2. 
Severity .......................................................................................................................63 
9.4.3.3. 
Action Taken with Study Drug ...................................................................................63 
9.4.3.4. 
Treatment Given for Adverse Event ...........................................................................64 
9.4.3.5. 
Outcome of the Adverse Event ...................................................................................64 
9.4.3.6. 
Follow-Up of Adverse Event ......................................................................................64 
9.4.3.7. 
Adjudication Committees ...........................................................................................65 
9.5. 
Procedures for Handling Special Situations ...............................................................65 
9.5.1. 
Abnormalities of Laboratory Tests .............................................................................65 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................66 
9.5.3. 
Dosing Errors ..............................................................................................................66 
9.5.4. 
Contraception and Pregnancy .....................................................................................66 
10. 
STATISTICAL CONSIDERATIONS .......................................................................67 
10.1. 
Stratification, Subsets, and Covariates .......................................................................67 
10.2. 
Sample Size Considerations .......................................................................................68 
10.3. 
Analysis Populations ..................................................................................................68 
10.4. 
Definition of Baseline and Primary Time Point .........................................................68 
10.5. 
Interim Analysis and Multiplicity ...............................................................................69 
10.6. 
Planned Methods of Analysis .....................................................................................71 
10.6.1. 
Demographic and Baseline Characteristics ................................................................72 
10.6.2. 
Safety Analysis ...........................................................................................................72 
10.6.3. 
Efficacy Analysis ........................................................................................................72 
10.6.3.1. 
Analysis of Primary Endpoint ....................................................................................72 
10.6.3.2. 
Analysis of Secondary Endpoints ...............................................................................74 
10.6.4. 
Pharmacokinetic and Anti-Drug Antibody Analysis ..................................................75 




ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
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LIST OF TABLES 
Table 1: 
Study Drug Characteristics .........................................................................................46 
Table 2: 
Actions in Patients with Low Platelet Count ..............................................................51 
Table 3: 
Additional Lab Analyses for Patients with Platelet Count Less Than 
50,000/mm3 .................................................................................................................52 
Table 4: 
Expected Event for the Protocol Defined Population by Preferred Term and 
Expected Incidence .....................................................................................................59 
 
 
LIST OF FIGURES 
Figure 1: 
A Schematic Overview of the Possible Effects of ApoC-III on TRL 
Metabolism .................................................................................................................25 
Figure 2: 
Design of ISIS 678354, a GalNAc3 Conjugated Chimeric 2′-MOE 
Phosphorothioate Oligonucleotide..............................................................................28 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
10 
PROTOCOL AMENDMENT 
Protocol Number: 
ISIS 678354-CS3 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of 
AKCEA‑APOCIII‑LRX Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
Amendment Number: 
9 
Amendment Date: 
2 August 2023 
The following table provides a summary list of modifications to Protocol ISIS 678354-CS3 
Amendment 8, dated 19 June 2023.  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 
Synopsis 
Section 1.1.2 
Section 1.2.2 
Section 10.5 
Interim Analysis 
and Multiplicity 
• 
The following secondary points were added: 
o Secondary endpoint:  comparison of adjudicated acute 
pancreatitis event rate during the Treatment Period 
(Week 1 through Week 53/ET) between pooled 
ISIS 678354 treatment group and pooled placebo in the 
subset of FAS with a prior history of pancreatitis within 
10 years prior to Screening 
o Secondary endpoint:  comparison of adjudicated acute 
pancreatitis event rate from Week 13 to Week 53 
between pooled ISIS 678354 treatment group and 
pooled placebo in the subset of FAS with a prior history 
of pancreatitis within 10 years prior to Screening 
• 
The following secondary endpoints were changed as noted 
with deletions in strike-through and additions in bold:  
o Secondary endpoint:  comparison of proportion of 
patients who achieve fasting TG ≤ 750880 mg/dL at the 
primary analysis time point between ISIS 678354 
80-mg treatment group and pooled placebo in the FAS 
o Secondary endpoint:  comparison of proportion of 
patients who achieve fasting TG ≤ 750880 mg/dL at the 
primary analysis time point between ISIS 678354 
50-mg treatment group and pooled placebo in the FAS 
• 
The testing sequence for the secondary endpoints was 
updated  
Endpoints were 
added in line with 
the stratification 
criteria of patients 
with a prior history 
of pancreatitis 
within 10 years 
prior to Screening. 
Endpoints were 
changed from 
achieving fasting 
TG ≤ 750 mg/dL to 
achieving fasting 
TG ≤ 880 mg/dL in 
line with the 
inclusion criteria of 
fasting TG 
≥ 880 mg/dL 
(10 mmol/L) at 
Screening. 


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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of 
AKCEA‑APOCIII‑LRX Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS) 
Study Phase 
3 
Indication 
Familial Chylomicronemia Syndrome 
Primary Objective 
To evaluate the efficacy of ISIS 678354 as compared to placebo on the percent 
change in fasting triglycerides (TG) from Baseline 
Secondary 
Objectives 
•
Percent change in fasting apoC-III from Baseline
•
Proportion of patients who achieve ≥ 40% reduction in fasting TG from 
Baseline
•
Percent change in fasting apoB-48 from Baseline
•
Percent change in fasting non-HDL-C from Baseline
•
Adjudicated acute pancreatitis event rate in patients with a prior history of 
pancreatitis within 10 years prior to Screening
•
Adjudicated acute pancreatitis event rate
•
Proportion of patients who achieve ≥ 70% reduction in fasting TG from 
Baseline
•
Proportion of patients who achieve fasting TG ≤ 880 mg/dL (10 mmol/L)
•
Adjudicated acute pancreatitis event rate in patients with ≥ 2 events of 
adjudicated acute pancreatitis in 5 years prior to enrollment
•
Proportion of patients who achieve fasting TG ≤ 500 mg/dL (5.7 mmol/L)
Additional / 
Exploratory 
Objectives 
Patient reported abdominal pain, other FCS-related symptoms, diet, and impacts, 
health-related quality of life (HRQoL), cognitive function, and emergency room 
(ER) visits, incidence of all-cause hospitalizations and total inpatient days 
Safety Objective 
To evaluate the safety and tolerability of ISIS 678354 
Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled study.  
Eligible patients will enter an approximately 4-week, but no more than 8-week, 
Screening Period that includes an at least 2-week diet stabilization/run-in period 
for patients not already on a stable diet, and an approximately 2-week 
qualification period.  Following qualification, approximately 60 eligible patients 
will be randomized 1:1 to Cohort A (50 mg) or Cohort B (80 mg) and each 
cohort further randomized 2:1 to receive ISIS 678354 or placebo in a 53-week 
Treatment Period.  Patients in Cohort A will receive 50 mg of ISIS 678354 once 
every 4 weeks or matching volume of placebo (0.5 mL) Weeks 1-49 of the 
Treatment Period.  Patients in Cohort B will receive 80 mg ISIS 678354 once 
every 4 weeks or matching volume of placebo (0.8 mL) Weeks 1-49 of the 
Treatment Period.  Randomization will be stratified by (1) prior history of 
pancreatitis (within 10 years prior to Screening) and (2) previous treatment with 
volanesorsen.  Dietary counseling will commence at the start of the diet 
stabilization period and will be reinforced at intervals throughout the Treatment 
and Follow-up Period.  Following the Week 53 visit, eligible patients may elect 
to enroll in an open-label extension (OLE) study pending study approval by the 
institutional review board/independent ethics committee (IRB/IEC) and the 
appropriate regulatory authority. 


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PROTOCOL SYNOPSIS (CONTINUED) 
Study Design 
(Continued) 
Patients not participating in the OLE will enter the 13-week Post-Treatment 
Evaluation Period.  The primary endpoint for the study will be evaluated after the 
last patient has completed the Week 53/ET Visit and will be based on the percent 
change in fasting TG from Baseline at the primary analysis time point (Month 6). 
Number of Patients Approximately 60 
Study Population 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all study 
requirements 
2. Aged ≥ 18 years at the time of informed consent 
3. A diagnosis of Familial Chylomicronemia Syndrome (type 1 
Hyperlipoproteinemia) by documentation of confirmed homozygote, 
compound heterozygote or double heterozygote for loss-of-function 
mutations in type 1-causing genes (such as LPL, GPIHBP1, APOA5, 
APOC2, GPD1, or LMF1) 
4. Fasting TG ≥ 880 mg/dL (10 mmol/L) at Screening.  If the fasting TG is 
< 880 mg/dL up to 2 additional tests may be performed with any single test 
used to qualify 
5. History of pancreatitis (defined as a recorded diagnosis of acute pancreatitis 
or hospitalization or emergency room (ER) visit for severe abdominal pain 
consistent with acute pancreatitis and for which no alternate diagnosis was 
made) within 10 years prior to Screening.  Patients without a recorded 
history of pancreatitis, or no recorded history within 10 years prior to 
Screening, are also eligible but their enrollment will be capped at 35% 
(i.e., ≤ 21 of the 60 planned patients) 
6. Willing to follow a diet comprising ≤ 20 g fat per day during the study 
7. Willing to complete all Patient Reported Outcome assessments throughout 
the study as described in Section 6.2.5 
 
 


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PROTOCOL SYNOPSIS (CONTINUED) 
Study Population 
(Continued) 
Inclusion Criteria (Continued) 
8. Satisfy the following: 
a. Females: must be non-pregnant and non-lactating and either: 
i. 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) 
ii. post-menopausal (defined as 12 months of spontaneous amenorrhea 
in females > 55 years of age or, in females ≤ 55 years, 12 months 
of spontaneous amenorrhea without an alternative medical cause 
and FSH levels in the postmenopausal range for the laboratory 
involved) 
iii. abstinent* or 
b. if engaged in sexual relations of child-bearing potential, agree to 
use a highly effective contraceptive method from the time of 
signing the informed consent form until at least 17 weeks after 
the last dose of Study Drug (ISIS 678354 or placebo)Males:  
Surgically sterile, abstinent*, or if engaged in sexual relations 
with a female of child-bearing potential, patient is utilizing a 
highly effective contraceptive method from the time of signing 
the informed consent form until at least 17 weeks after the last 
dose of Study Drug (ISIS 678354 or placebo) 
* 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 
9. Atypical antipsychotic medications (e.g., olanzapine and clozapine) will be 
allowed if on a stable dose for at least 3 months prior to Screening and dose 
and regimen expected to remain constant through the end of their 
participation in this study 
10. The following concomitant medications will be allowed if on a stable dose 
for at least 4 weeks prior to Screening and dose and regimen expected to 
remain constant through the end of their participation in this study 
(occasional or intermittent use of over-the-counter (OTC) medications will 
be allowed at Investigator’s discretion): 
a. Statins, omega-3 fatty acids (prescription and OTC), fibrates, or other 
lipid-lowering medications.  Patients taking OTC omega-3 fatty acids 
should make every effort to remain on the same brand through the end 
of the study 
b. Antidiabetic medications 
c. Antihypertensive medications 
d. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and 
apixaban) and regular clinical monitoring is performed 
e. Tamoxifen, estrogens or progestins 
 
 


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PROTOCOL SYNOPSIS (CONTINUED) 
Study Population 
(Continued) 
Exclusion Criteria 
1. 
Clinically significant abnormalities in medical history (e.g., previous acute 
coronary syndrome within 6 months of Screening, major surgery within 
3 months of Screening) or physical examination 
2. 
Active pancreatitis within 4 weeks prior to Screening 
3. 
Screening laboratory results as follows, or any other clinically significant 
abnormalities in screening laboratory values that would render a patient 
unsuitable for inclusion: 
a. Platelet count < 100K/mm3 at Screening or Qualification.  If the platelet 
count is < 100K/mm3 up to 2 additional tests may be performed to 
qualify at both Screening and Qualification 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 3.0 × upper limit of normal (ULN) 
c. Total bilirubin > ULN unless due to Gilbert’s syndrome 
d. Estimated GFR< 45 mL/min/1.73 m2 [as determined by the CKD-EPI 
formula for creatinine clearance; (Levey et al. 2009)] 
e. Urine protein/creatinine ratio (UPCR) ≥ 500 mg/g or urine 
albumin/creatinine ratio (UACR) ≥ 300 mg/g 
4. 
Uncontrolled arterial hypertension (blood pressure [BP] > 160/100 mmHg) 
5. 
History of bleeding diathesis or coagulopathy or clinically significant 
abnormality in coagulation parameters at Screening 
6. 
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 
7. 
Active infection with human immunodeficiency virus (HIV), hepatitis C or 
hepatitis B diagnosed by initial serological testing and confirmed with 
RNA testing, or prior treatment for hepatitis C.  Patients at Screening who 
test positive by serology, but negative by RNA may be allowed in 
consultation with the Sponsor Medical Monitor 
8. 
Malignancy within 5 years, except for basal or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix that has been successfully 
treated.  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 
9. 
Blood donation of 50 to 499 mL within 30 days of Screening or of 
> 499 mL within 60 days of Screening 
10. 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 
11. 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 
 
 


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PROTOCOL SYNOPSIS (CONTINUED) 
Study Population 
(Continued) 
Exclusion Criteria (Continued) 
12. 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 
b. Plasma apheresis within 4 weeks prior to Screening or planned during 
the study 
13. Unwillingness to comply with study procedures, including follow-up, as 
specified by this protocol, or unwillingness to cooperate fully with the 
Investigator 
14. Have any other conditions, which, in the opinion of the Investigator would 
make the patient unsuitable for inclusion, or could interfere with the 
patient participating in or completing the Study 
Treatment Groups 
Cohort A (n = 30):  Patients will be randomized 2:1 to receive 50 mg 
ISIS 678354 or matching volume of placebo SC once every 4 weeks for 
Weeks 1-49. 
Cohort B (n = 30):  Patients will be randomized 2:1 to receive 80 mg 
ISIS 678354 or matching volume of placebo SC once every 4 weeks for 
Weeks 1-49. 
Study Drug 
Administration 
ISIS 678354 or placebo will be administered as subcutaneous (SC) injections. 
Rationale for Dose 
and Schedule 
Selection 
Doses of 50 mg or 80 mg once every 4 weeks were chosen based on the 
pre-clinical data and the pharmacodynamic and safety analysis of the Phase 1 
study in healthy volunteers with hypertriglyceridemia and the Phase 2 study in 
patients with hypertriglyceridemia and established cardiovascular disease 
(CVD) or at high risk for CVD.  
Study Visit Schedule 
and Procedures 
The study for an individual patient will generally consist of the following 
periods: 
• 
An approximately 4-week, but no more than 8-week, Screening Period 
• 
A 53-week Treatment Period during which Study Drug will be 
administered as a once every-4-week SC injection (Week 1 through 
Week 49) 
• 
A 13-week Post-Treatment Evaluation Period or transition to OLE Study 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events (AE), 
concomitant medication/procedure information, lipid panel, ISIS 678354 
plasma trough concentrations, anti-drug antibody (ADA) testing, 
electrocardiogram (ECGs), and patient reported outcome (PRO) assessments 
will be performed according to the schedule of procedures in Appendix A.  
Dietary counseling will commence at the start of the diet stabilization period 
and will be repeated at intervals throughout the Treatment and Follow-up 
Period.  Following the Week 53 visit, eligible patients may elect to enroll in the 
OLE study pending study approval by the IRB/IEC and the appropriate 
regulatory authority.  Patients not participating in the OLE will enter the 
13-week Post-Treatment Evaluation Period 


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PROTOCOL SYNOPSIS (CONTINUED) 
Primary Endpoint 
The primary endpoint is the percent change in fasting TG from Baseline at 
6 months (average of Weeks 23, 25 and 27) compared to placebo 
Secondary Endpoints Secondary endpoints include the following: 
• 
Percent change in fasting TG from Baseline at 12 months (average of 
Week 51 and Week 53) compared to placebo 
• 
Percent change in fasting apoC-III from Baseline at 6 months compared to 
placebo 
• 
Percent change in fasting apoC-III from Baseline at 12 months compared to 
placebo 
• 
Proportion of patients who achieve ≥ 40% reduction in fasting TG from 
Baseline at 6 months compared to placebo 
• 
Percent change in fasting apoB-48 from Baseline at 6 months compared to 
placebo 
• 
Percent change in fasting non-HDL-C from Baseline at 6 months compared 
to placebo 
• 
Adjudicated acute pancreatitis event rate during the Treatment Period 
(Week 1 through Week 53) compared to placebo, in patients with a history 
of pancreatitis within 10 years prior to Screening 
• 
Adjudicated acute pancreatitis event rate during the Treatment Period 
(Week 1 through Week 53) compared to placebo 
• 
Adjudicated acute pancreatitis event rate from Week 13 through Week 53 
compared to placebo in patients with a history of pancreatitis within 
10 years prior to Screening 
• 
Adjudicated acute pancreatitis event rate from Week 13 to Week 53 
compared to placebo 
• 
Proportion of patients who achieve ≥ 70% reduction in fasting TG from 
Baseline at 6 months compared to placebo 
• 
Percent change in fasting non-HDL-C from Baseline at 12 months 
compared to placebo 
• 
Percent change in fasting apoB-48 from Baseline at 12 months compared to 
placebo 
• 
Proportion of patients who achieve fasting TG ≤ 880 mg/dL at 6 months 
compared to placebo 
• 
Adjudicated acute pancreatitis event rate during the Treatment Period 
(Week 1 through Week 53) compared to placebo, in patients with 
≥ 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment 
• 
Adjudicated acute pancreatitis event rate from Week 13 to Week 53 
compared to placebo, in patients with ≥ 2 events of adjudicated acute 
pancreatitis in 5 years prior to enrollment 
• 
Proportion of patients who achieve fasting TG ≤ 500 mg/dL at 6 months 
compared to placebo 
Additional/ 
Exploratory 
Endpoints 
Frequency and severity of patient-reported abdominal pain and other 
FCS-related symptoms, diet, and impacts, HRQoL, cognitive function, and ER 
visits, incidence of all-cause hospitalizations and total inpatient days, compared 
to placebo 


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PROTOCOL SYNOPSIS (CONTINUED) 
Safety Endpoints 
Safety and tolerability assessments include adverse events, clinical laboratory 
tests, ECGs, use of concomitant medications, and independently adjudicated 
events rates of Major Adverse Cardiovascular Events (MACE) for ISIS 678354 
as compared to placebo 
Statistical 
Considerations 
Sample Size Considerations:  Based upon prior clinical trial experience with 
FCS patients, the standard deviation (SD) of the percent change from Baseline 
in TGs is approximately 46%.  With 14 patients in each ISIS 678354 treatment 
group and 14 in the pooled placebo group, there would be a 90% power to 
detect a 60% difference between each ISIS 678354 treatment group and pooled 
placebo group at an alpha level of 0.05 (two-sided), assuming 60% reduction in 
the ISIS 678354 treatment patients and no change in the placebo patients.  
Approximately 60 patients will be enrolled in this trial to account for potential 
early dropouts and to facilitate safety evaluations. 
Eligible patients will be randomized 1:1 to Cohort A or Cohort B and each 
cohort further randomized 2:1 (ISIS 678354:placebo) and stratified for: 
• 
Prior history of pancreatitis within 10 years prior to Screening* vs. no 
history of pancreatitis or no history within 10 years prior to Screening 
• 
Previous treatment with volanesorsen 
* History of pancreatitis is defined as a recorded diagnosis of acute pancreatitis 
or hospitalization or ER visit for severe abdominal pain consistent with acute 
pancreatitis and for which no alternate diagnosis was made 
Sponsor/Licensee 
Ionis Pharmaceuticals, Inc. / Akcea Therapeutics, Inc. 




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STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
ANA 
antinuclear antibody 
apoB-48 
apolipoprotein B-48 
apoC-III 
apolipoprotein C-III 
aPTT 
activated partial thromboplastin time 
ASGPR 
asialoglycoprotein receptor 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase  
AUC 
area under the curve 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CAD 
coronary artery disease 
CIR 
copy increment from reference 
CL 
systemic clearance 
Cmax 
maximum concentration 
CRP 
c-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events  
CVD 
cardiovascular disease 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated GFR 
FAS 
full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
GalNAc3 
triantenary N-acetyl galactosamine  
GCP 
Good Clinical Practice 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRQoL 
health-related quality of life 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IDL 
intermediate density lipoprotein 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IM 
immunogenicity 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISIS 678354 
antisense inhibitor of apoC-III 
LDL 
low-density lipoprotein 


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LLN 
lower limit of normal 
LMF1 
lipase maturation Factor 1 
MACE 
major adverse cardiovascular event 
MAD 
multiple-ascending dose 
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-cholesterol 
NSAID 
non-steroidal anti-inflammatory drug 
OLE 
open-label extension 
on study 
The patient is ‘on study’ from signing of the informed consent until their last study visit 
OTC 
over-the-counter 
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 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
siRNA 
small interfering ribonucleic acid 
Study Day 1 
defined as the first day Study Drug product is administered to the patient 
Study Drug 
ISIS 678354 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment-emergent adverse event 
TG 
triglycerides  
TRL 
TG-rich lipoproteins 
UACR 
urine/albumin creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein/creatinine ratio 
VLDL 
very low-density lipoprotein 




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1.2.2. 
Secondary Endpoints 
The secondary endpoints include the following: 
• Percent change in fasting TG from Baseline at 12 months (average of Weeks 51 
and 53) compared to placebo 
• Percent change in fasting apoC-III from Baseline at 6 months compared to placebo 
• Percent change in fasting apoC-III from Baseline at 12 months compared to placebo 
• Proportion of patients who achieve ≥ 40% reduction in fasting TG from Baseline at 
6 months compared to placebo 
• Percent change in fasting apoB-48 from Baseline at 6 months compared to placebo 
• Percent change in fasting non-HDL-C from Baseline at 6 months compared to 
placebo 
• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1 
through Week 53) compared to placebo, in patients with a prior history of pancreatitis 
within 10 years prior to Screening 
• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1 
through Week 53) compared to placebo 
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to 
placebo in patients with a prior history of pancreatitis within 10 years prior to 
Screening 
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to 
placebo 
• Proportion of patients who achieve ≥ 70% reduction in fasting TG from Baseline at 
6 months compared to placebo 
• Percent change in fasting non-HDL-C from Baseline at 12 months compared to 
placebo 
• Percent change in fasting apoB-48 from Baseline at 12 months compared to placebo 
• Proportion of patients who achieve fasting TG ≤ 880 mg/dL at 6 months compared to 
placebo 
• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1 
through Week 53) compared to placebo, in patients with ≥ 2 events of adjudicated 
acute pancreatitis in 5 years prior to enrollment 
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to 
placebo in patients with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment 
• Proportion of patients who achieve fasting TG ≤ 500 mg/dL at 6 months compared to 
placebo 


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1.2.3. 
Additional/Exploratory Endpoints 
Exploratory endpoints include the following: 
• Frequency and severity of patient-reported abdominal pain and other FCS-related 
symptoms (including physical fatigue, difficulty thinking and diarrhea), diet, and 
impacts, HRQoL, cognitive function, (Appendix E) and ER visits, incidence of 
all-cause hospitalizations and total inpatient days, compared to placebo 
1.2.4. 
Safety Endpoints 
Safety and tolerability assessments include adverse events, clinical laboratory tests, 
electrocardiogram (ECGs), use of concomitant medications, and independently adjudicated event 
rate of MACE for ISIS 678354 as compared to placebo. 
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia.  It is a rare autosomal recessive disease that can be 
diagnosed either in childhood or adulthood. 
FCS is characterized by frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and in children, can result in a failure to thrive 
(Brunzell 1999; Tremblay et al. 2011).  Physical examination frequently reveals eruptive 
xanthomas, lipemia retinalis and hepatosplenomegaly, and plasma from patients appears 
lactescent, interfering with determination of other laboratory parameters (Tremblay et al. 2011).  
Fasting plasma TG levels in FCS patients are typically 10-fold to 100-fold above normal 
(1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 15-20% 
of daily calorie intake) (Brunzell 1999). 
Patients with FCS often present in infancy or childhood with recurrent episodes of abdominal 
pain or pancreatitis, eruptive xanthomas or hepatomegaly.  The diagnosis of FCS is then 
established by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) enzyme 
activity in post-heparin plasma (Brunzell 1999). 
Patients with FCS carry a heavy burden of medical complications, the most serious being an 
extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent episodes of acute 
pancreatitis, these patients may also develop chronic pancreatitis and signs of exocrine or 
endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  While the 
pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, one hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed 
to pancreatic lipase, resulting in release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012). 
FCS significantly affects patients’ HRQoL.  Bloating, generalized abdominal pain, asthenia, 
anxiety about potential painful attacks and overall health, difficulty concentrating and “brain 


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fog” are commonly reported symptoms of FCS.  The psychosocial burden of FCS is also 
increased by dietary fat restriction and overall interference with social interactions and ability to 
work (Davidson et al. 2017; Gelrud et al. 2017; Davidson et al. 2018; Fox et al. 2020). 
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective TG 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
TGs in chylomicrons along the luminal surface of capillaries, mainly in heart, skeletal muscle, 
and adipose tissue, promoting TG clearance from the circulation.  LPL is regulated by a number 
of key genes, and loss-of-function mutations in one of these genes, or the LPL gene itself, results 
in FCS (Surendran et al. 2012).  In addition to loss of function mutations, null mutations, and 
nonsense mutations in the LPL gene, other genes currently identified in FCS patients, and known 
to directly influence LPL activity include:  apolipoprotein C-II (APOC2) a cofactor for LPL 
(Schuster et al. 2011); apolipoprotein A-V (APOA5) (Schaap et al. 2004); lipase maturation 
Factor 1 (LMF1), a transmembrane protein involved in LPL maturation (Doolittle et al. 2009), 
glycosylphosphotidylinositol-anchored HDL-binding protein 1 (GP1HBP1), a capillary 
endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons 
(Beigneux et al. 2007). 
2.2. 
Therapeutic Rationale 
Apolipoprotein C-III (ApoC-III), a key regulator of plasma TG levels, is a 79 amino acid 
glycoprotein synthesized principally in the liver (Gordts et al. 2016), (Figure 1).  ApoC-III is a 
major regulator of lipoprotein metabolism and plays a pivotal role in regulating plasma TG levels 
(Chan et al. 2008).  It is a component of TG-rich lipoproteins (TRLs) and a potent inhibitor of 
LPL (Lemieux et al. 2003).  At higher concentrations apoC-III also inhibits hepatic lipase 
activity (Kinnunen and Ehnolm 1976), an enzyme which plays an important role in the 
conversion of dense very low-density lipoprotein (VLDL) to intermediate density 
lipoprotein (IDL) and to low-density lipoprotein (LDL) (Mann et al. 1997; 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 
(Mann et al. 1997).  Thus, elevated plasma apoC-III levels are associated with impaired 
hydrolysis and retarded clearance of TG-rich particles, resulting in the accumulation of 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, LDLR = LDL receptor, 
LPL = lipoprotein lipase, LRP1 = low-density lipoprotein receptor related protein 1, SDC1 = syndecan-1, 
VLDL = very low-density lipoprotein. 
 
Mechanistically, FCS is primarily a consequence of ineffective clearance of TRL.  ApoC-III is a 
prominent component of TRL (e.g., VLDL and chylomicrons).  In addition to its role in 
inhibiting LPL, apoC-III inhibits TRL remnant (TG-depleted remnant lipoprotein) uptake by 
hepatic lipoprotein receptors by steric inhibition of the interaction of apoE with these receptors. 
Human genetic data have demonstrated positive 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 


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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) 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.  Taken together, the available data strongly support the development of a therapy that 
reduces plasma apoC-III levels in order to reduce the very high circulating TG and chylomicron 
levels that are accompanied by increasing risk for acute pancreatitis. 
The mechanistic data available to date on apoC-III function indicates that lowering apoC-III will 
produce clinically relevant reductions in TGs as observed with ISIS 678354 treatment in healthy 
volunteers and in patients with high TGs.  In particular, because apoC-III inhibits clearance of 
TRL in uptake in the liver, a mechanism independent of LPL activity, it will lower TG levels 
even in patients with FCS who lack any LPL activity.  This was clearly demonstrated with the 
profound reductions in TGs observed with volanesorsen, another antisense inhibitor of apoC-III, 
in patients who had absent or very low LPL activity (Witztum et al. 2019).  Therefore, 
ISIS 678354 is expected to effectively lower TG levels in FCS patients and may have the 
potential to reduce events of pancreatitis in this patient population.  To this end, volanesorsen 
was granted approval in the European Union on 3 May 2019. 
2.3. 
ISIS 678354 
ISIS 678354 is an antisense oligonucleotide (ASO) inhibitor of apoC-III production.  
Specifically, ISIS 678354 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 ISIS 678354, 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; 2015).  ISIS 678354, 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.  ISIS 678354, 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 ISIS 678354 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. 


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2.3.2. 
Chemistry 
Chemically, ISIS 678354 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. 
The nucleotide sequence of ISIS 678354 (Figure 2) is fully complementary to base-pair positions 
489-508 (within the 3′ non-translated sequence of the apoC-III mRNA) and binds to the mRNA 
by Watson-Crick base pairing.  Based on in silico analysis, it is not predicted to target any other 
human gene.  Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides 
at the 5′ end and the 5 nucleotides at the 3′ end are composed of 2′-O-(2-methoxyethyl) 
(2′-MOE)-modified ribonucleotides.  These MOE-modified nucleotides confer (1) increased 
affinity for the target mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance 
to exonucleases and endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), 
and (3) amelioration of some of the high-dose toxicities thereby resulting in an improved safety 
profile compared to first generation antisense drugs containing phosphorothioate-modified 
oligodeoxynucleotides (DNA) (Henry et al. 2000).  The third region, the central portion of the 
oligonucleotide, is composed of 10 oligodeoxynucleotides.  This chimeric design is called a 
MOE-gapmer, and ISIS 678354 employs this chimeric structure to enable use of the 
RNase H1-mechanism for antisense activity.  This is because while the 2′-MOE modification 
confers increased stability and affinity, it does not support RNase H1-catalyzed cleavage of RNA 
hybridized to 2′-MOE-modified nucleotides (McKay et al. 1999).  This is caused by 
conformational changes induced in the heteroduplex by 2′-alkoxy:RNA hybrids that are not 
recognized by RNase H1 enzymes (Inoue et al. 1987; Monia et al. 1993).  By limiting the 
2′-MOE modification to nucleotides flanking the phosphorothioate oligodeoxynucleotide core, 
the beneficial attributes of the 2′-MOE chemistry are preserved while also retaining RNase H1 
recognition. 
The fourth region is comprised of a cluster of GalNAc3 sugars which is linked to the 5′-end of 
ISIS 678354 via a phosphodiester linkage.  The GalNAc3 cluster is a high affinity ligand for the 
ASGPR, a receptor expressed primarily on the surface of liver hepatocytes (Stockert 1995).  The 
GalNAc3 cluster enhances delivery of ISIS 678354 to liver hepatocytes over other cell types and 
enhances potency.  After internalization into cells, the GalNAc3 cluster is metabolized to release 
‘free ASO’ inside the cell (Prakash et al. 2014). 


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Figure 2: 
Design of ISIS 678354, a GalNAc3 Conjugated Chimeric 2′-MOE 
Phosphorothioate Oligonucleotide 
 
2.3.3. 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ISIS 678354 can be 
found in the Investigator’s Brochure. 
General toxicology and pharmacokinetic (PK) studies for ISIS 678354 included sub-chronic 
(13-week repeat-dose studies with a 13-week recovery) and chronic (26-week in mice with a 
13-week recovery and 39-week in monkey with a 26-week recovery) toxicity studies.  
ISIS 838707 (mouse-specific apoC-III inhibitor) was also included in the chronic toxicity study 
in mice to evaluate any potential toxicity associated with apoC-III inhibition.  The following 
findings in the ISIS 678354 mouse and monkey studies are considered non-specific class effects 
related to the uptake and accumulation of 2′-MOE ASOs, and the targeted delivery of ASO to the 
hepatocytes by the GalNAc3 conjugate which results in higher hepatocellular concentrations 
compared to unconjugated 2′-MOE ASOs.  This is most apparent in mice at doses of 20 and 
24 mg/kg/wk and in monkey at doses of 12 and 30 mg/kg/wk. 
• dose-dependent microscopic findings related to ASO tissue accumulation included 
the presence of basophilic granules in various tissues in mice and monkeys (liver, 
kidney, lymph node, bone marrow and skin/injection sites) resulting in adaptive 
responses such as hypertrophy and/or vacuolation at 30 mg/kg/wk. 
• in mice, dose-dependent increases in mitotic figures, cytoplasmic alteration and 
karyomegaly of hepatocytes and/or infiltration by vacuolated/granular macrophages 
predominantly at ≥ 6 mg/kg/wk (~50 to ~100 mg/wk human equivalent dose (HED) 
assuming 70 kg human body weight and 5- to 8-fold scaling factor for mouse plasma 
PK established for 2′-MOE ASO; (Yu et al. 2015), and mild-to-occasionally marked 
increases in ALT (~6.5-fold over control) and/or AST (~2.6-fold over control) 
predominantly at 20 mg/kg/wk (~165 to 350 mg/wk HED).  Individual hepatocellular 
necrosis was observed in one male at 20 mg/kg/wk after 26 weeks of treatment which 
correlated with an increase in ALT and AST. 
2′-MOE 
2′-MOE 
2′-Deoxy 
GalNAc3 = THA-GalNAc cluster 
2′-MOE = 2′-methoxylethyl RNA 
2′-Deoxy = DNA 
s = phosphorothioate linkage 
o = phosphodiester linkage 
(RNase H1 sensitive) 
GalNAc3 
oAsGsCsTsTs 
CsTsTsGsTsCsCsAsGsCs 
TsTsTsAsC 


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• in monkeys, compared to baseline values, increases in glutamate dehydrogenase 
(GLDH) and ALT (up to ~5- and 4-fold over control, respectively) were observed at 
≥ 6 mg/kg/wk (420 mg/wk HED assuming 70 kg human body weight and direct 
scaling to humans on the basis of body weight) after 39 weeks of treatment with no 
microscopic correlates. 
• pro-inflammatory changes in mice and monkeys after up to 26 and 39 weeks of 
treatment, respectively, included slight increases in liver weights (up to ~1.6- and up 
to ~2.1-fold over control) mainly at ≥ 6 and ≥ 12 mg/kg/wk in mice and monkeys, 
respectively.  Increased spleen weights (up to ~1.9- and up to ~2.5-fold over control) 
were also observed mainly at ≥ 6 and ≥ 12 mg/kg/wk in mice and monkeys, 
respectively.  In mice, increased MCP-1 (up to 7.7-fold over control) was 
accompanied by splenomegaly and multi-organ vacuolated/granular macrophage 
infiltrates in the 20 mg/kg/wk dose group. 
• in monkeys, sporadic incidences of minimal to marked mononuclear cell infiltration 
at injection site skin were seen in all dose groups. 
The most noteworthy finding in the monkey study was a marked platelet (PLT) reduction, which 
occurred in 1 male monkey at the mid-high dose level, 12 mg/kg/wk (840 mg/wk HED).  At 
Day 65, this animal presented with petechia and oral mucosal bleeding with a PLT count of 
8 × 103/μL.  This animal was treated with methylprednisolone on Days 65 and 72, and the PLT 
count quickly recovered to 145 × 103/μL on Day 70.  This animal continued treatment with 
ISIS 678354, without a dosing holiday, until scheduled necropsy on Day 93 (interim) with the 
last clinical pathology evaluation on Day 93 again showing a marked reduction in PLT count 
(6 × 103/μL).  Marked PLT reductions were not observed in the 30 mg/kg/wk dose group 
(2100 mg/wk HED) for up to 13 weeks or in any of the remaining dose groups for up to 
39 weeks.  
In vivo safety pharmacology and in vitro genetic toxicity studies indicate that ISIS 678354:  
• had no effects on cardiovascular (blood pressure [BP], heart rate [HR], ECG), 
respiratory (respiration rate, arterial blood gases), or central nervous system (CNS) 
parameters in the monkey consistent with previous experience with 2ʹ-MOE ASOs 
(Kim et al. 2014). 
• was not genotoxic and did not increase the rate of mutations in the in vitro bacterial 
reverse mutation assay nor induce chromosomal abnormalities in mammalian cells. 
2.3.4. 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 678354 can be found in 
the Investigator’s Brochure.  A summary of the studies that has been conducted with 
ISIS 678354 is included below. 
ISIS 678354-CS1 was a Phase 1, double-blind, placebo-controlled, dose-escalation study 
designed to assess the safety, tolerability and PK of single and multiple doses of ISIS 678354 
administered by subcutaneous (SC) injection to healthy subjects (age 18 to 65).  In the 
single-ascending dose (SAD) part of the study, 5 dose levels (10, 30, 60, 90, and 120 mg) were 
evaluated sequentially.  In the multiple-ascending dose (MAD) part, 2 dose levels (15 and 


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30 mg) were evaluated at weekly dosing for 6 weeks and 1 dose level (60 mg) was evaluated at 
every-4-week dosing for 3 months.  The SAD and weekly MAD dose levels were studied in a 
cohort of 8 subjects, where 6 were randomized to active treatment with ISIS 678354 and 2 were 
randomized to placebo.  In the every-4-week MAD cohort 10 subjects were studied (6 active and 
4 placebo).  In the 90 and 120 mg SAD and all of the MAD cohorts, the pharmacodynamic 
effects of ISIS 678354 vs. placebo were examined in healthy subjects with elevated triglycerides 
(TG > 200 mg/dL). 
Results from the SAD portion of the Phase 1 study showed significant dose-dependent sustained 
reductions in fasting total apoC-III and TG levels.  ApoC-III reductions of -4%, -32%, -65%, 
-78%, and -91%, and TG reductions of -12%, -11%, -43%, -68%, and -77% were observed with 
single doses of 10, 30, 60, 90 and 120 mg of ISIS 678354, respectively, 14 days after dosing.  In 
the MAD cohorts, mean apoC-III reductions of -65%, -84%, and -83% and mean TG reductions 
of -61%, -71%, and -65% were observed in the 15 and 30 mg weekly and 60 mg every 4-week 
dosing cohorts, respectively, 1 week after the last dose.  Significant dose-dependent reductions of 
up to ~ -30% in apoB and increases of up to ~100% in HDL-C were also observed.  There were 
no notable increases in LDL-C in any dose group.  Effects were sustained for at least 4 weeks 
after the last dose, consistent with the drug’s long terminal elimination half-life. 
Overall, ISIS 678354 was well-tolerated and there were no safety concerns.  There were no 
deaths, no serious AEs (SAE) related to ISIS 678354, no AEs leading to treatment 
discontinuation, and no clinically significant trends in laboratory assessments observed in any of 
the ISIS 678354 Phase 1 dose groups.  Two (2) of 6 subjects receiving ISIS 678354 every 
4 weeks, each experienced ALT increased (1 event in each subject of moderate severity) and 
single events of AST increased.  These events were considered possibly related to Study Drug 
and were the only events experienced by more than 1 subject receiving ISIS 678354 in the every 
4-weeks multiple-dose cohort.  Both subjects had prior history of AST and ALT elevations 
suggesting a medical history that may have contributed to the observed liver enzyme elevations 
during the study.  Also, other dose cohorts with similar cumulative doses, the 120 mg single dose 
and 30 mg weekly dose, were not associated with increases in AST or ALT.  There were no other 
treatment-related laboratory abnormalities in the liver, kidney function or platelet counts and no 
clinically significant changes in vital signs or ECGs in any cohort studied. 
The Phase 2 study was a multicenter, randomized, double-blind, placebo-controlled, 
dose-ranging study.  A total of 114 patients with established cardiovascular disease (CVD), or 
being at risk for CVD, with fasting TG levels of ≥ 200 mg/dL and ≤ 500 mg/dL, and on 
standard-of-care preventative therapy for their known CVD risk factors were randomly assigned 
to 1 of the 4 parallel dosing cohorts, with each cohort having a 4:1 ratio to receive ISIS 678354 
or matching volume of placebo, respectively, by SC injection for up to 12 months.  The study 
evaluated 3 different doses of ISIS 678354: 10, 15, and 50 mg, and 3 different dosing regimens: 
weekly, every 2 weeks, and every 4 weeks (Q4W).  The range of dosing covered the equivalent 
monthly drug exposure of 10 mg to 50 mg.  Treatment duration was 6 to 12 months.  The 
treatment portion of the study was complete when the last patient reached 6 months of exposure.  
All patients then entered a 13-week Post-Treatment Follow-up Period. 
The primary efficacy analysis for the primary endpoint was the pairwise comparison of percent 
change from Baseline to the primary analysis time point in fasting TG between 
ISIS 678354-treated groups and pooled-placebo group.  The primary efficacy analysis time point 


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was at Week 25 for patients who received every 4-week dosing and at Week 27 for patients who 
received every 2-week or weekly dosing. 
Mean (95%CI) exposure to ISIS 678354 was 243.7 (222, 265) days.  Treatment compliance was 
high (over 90%) in all treatment groups.  Mean (standard deviation [SD]) baseline TG level for 
all 114 randomized patients was 284.7 (85.10) mg/dL, almost 2 times exceeding upper normal 
level of 149 mg/dL. 
The study met the primary efficacy endpoint.  Significant reductions in fasting TG levels from 
Baseline to the primary analysis time point were observed in all ISIS 678354-treated groups 
compared to placebo.  The highest dose group (50 mg Q4W) achieved mean 62% reduction from 
Baseline in fasting TG levels compared to placebo, associated with mean 74% reduction from 
Baseline in apoC-III 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 and there were no safety concerns.  Overall incidence and 
severity of treatment-emergent adverse event (TEAEs) “on-treatment” (defined as period from 
first dose through 1 dosing interval post-last dose) were comparable between the pooled placebo 
group and the pooled ISIS 678354 group.  Majority of TEAEs were mild, and none of severe 
TEAEs was considered related to the Study Drug.  The most frequently reported TEAE in the 
pooled ISIS 678354 group was injection site erythema (15.6%).  Treatment emergent SAEs were 
experienced by 4.2% patients in the placebo group and 10.0% patients in the pooled ISIS 678354 
group, none of them was considered related to the Study Drug.  Treatment discontinuations due 
to TEAEs were very infrequent (overall 3 patients), and well-balanced between the pooled 
placebo group (4.2%) and the pooled ISIS 678354 group (2.2%).  
There was 1 death on the study in 15 mg Q2W ISIS 678354 group:  patient with advanced CVD 
and other medical history including coronary artery disease (with ST-elevation MI, CABG, 
multiple, 10 in total, stent placement), congestive heart failure, aortic stenosis, carotid artery 
disease, and type 2 diabetes mellitus, died at home, no autopsy performed, death was considered 
as “heart related”. 
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 count were observed, and no patient had a 
confirmed platelet count < 100,000/mm3.  The incidence of minor bleeding events was 
comparable between the pooled placebo group (20.8%) and the pooled ISIS 678354 group 
(12.2%).  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%). 


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Treatment with AKCEA-APOCIII-LRx was not associated with any clinically significant changes 
in other laboratory parameters (including coagulation panel, and inflammatory marker, hsCRP), 
vital signs, or ECG parameters. 
2.4. 
Rationale for Dose and Schedule of Administration 
The starting dose and dosing regimens selected for this study are 50 mg or 80 mg every 4 weeks, 
which is supported by both the cumulative nonclinical data available to date and the Phase 1 and 
Phase 2 clinical data, as well as the medical need for maximal TG reduction for the highest 
proportion of FCS patients to get below the pancreatitis threshold of 750 mg/dL.  The 
APPROACH trial demonstrated that volanesorsen mediated lowering of plasma 
apolipoprotein C-III levels in subjects with FCS effectively lowered plasma TGs below the 
threshold of 750 mg/dL that has been associated with TG-induced acute pancreatitis (Berglund et 
al. 2012; Brown et al. 2012; Scherer et al. 2014; Valdivielso et al. 2014; Brahm and Hegele 
2015; Jacobson et al. 2015; Catapano et al. 2016; Witztum et al. 2019).  Based on preclinical 
pharmacodynamic data with ISIS 678354, a dose of 80 mg will likely maintain TG levels below 
750 mg/dL in a statistically significant number of subjects.  This opportunity to achieve a TG 
level below 750 mg/dL will help maximize the opportunity to provide a potential impact on the 
risk of pancreatitis. 
In nonclinical studies, ISIS 678354 demonstrated good safety profiles in rodents and monkeys.  
No nonclinical findings were considered to be related to the pharmacologic inhibition of 
apoC-III.  In the monkey, the No Observed Adverse Effect Level (NOAEL) was defined by the 
cumulative clinical pathology results and histopathology data which provide an adequate clinical 
margin.  The safety margins between the NOAEL in monkeys and the clinically relevant 
exposure are based on cumulative plasma AUC measurements (Yu et al. 2015) or mg/kg scaling 
(FDA 2005; Geary et al. 1997).  The NOAEL in monkeys was determined to be 6 mg/kg/wk 
(1680 mg/month HED assuming 70 kg human body weight; AUC0-48:  141 µg·h/mL).  This 
NOAEL is approximately 21-fold above the current highest proposed clinical dose 
(80 mg/month: estimated AUC0-tau:  6.7 µg·h/mL).  Clinical safety data to date suggest that 
ISIS 678354 has been well-tolerated at dose levels up to 30 mg every week (equivalent to 
120 mg every 4 weeks) in patients with high TGs with the most common AEs being local to the 
injection site and predominantly mild.  A pooled analysis of safety for the Phase 1 and Phase 2 
studies did not demonstrate any clear difference in safety or tolerability between the different 
doses tested (Phase 1:  10 mg, 30 mg, 60 mg, 90 mg, and 120 mg single dose, and 15 mg and 
30 mg per week for 6 weeks (i.e., 60 mg and 120 mg cumulative monthly equivalents, 
respectively), and 60 mg every 4-weeks for 13 weeks.  Phase 2:  10 mg and 50 mg every 
4 weeks, 15 mg every 2 weeks, and 10 mg every week, all for at least 6 months and up to 1 year). 
Analysis of the cohorts in which ISIS 678354 was studied at different dose levels demonstrates 
dose-dependent pharmacology with respect to pharmacodynamic effect on the target, apoC-III, 
with a clear difference in the TG-lowering effect between the different doses in the 10 mg to 
120 mg per month equivalent dose range as compared to placebo.  Considering the medical need 
for FCS patients with extremely high TG levels, often > 2000 mg/dL, achieving a maximal TG 
reduction over 70%, the level of reduction observed for volanesorsen at 300 mg every week 
dosing, is considered sufficient and necessary for ISIS 678354 to prevent the risk of acute 


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pancreatitis.  Population PK/PD model-based simulations for a population of FCS patients 
predicted 70% reduction in TGs and 86% reduction in apo-CIII for 80 mg every 4-week dosing. 
In addition to the nonclinical and clinical experience of ISIS 678354, the dose and schedule of 
administration is supported by the preclinical and clinical safety experience of several other 
2′-MOE-modified, GalNAc3-conjugated ASOs that have been safely administered SC in multiple 
clinical studies at doses up to 120 mg weekly for 12 weeks (ClinicalTrials.gov NCT03020745) 
and 20 mg weekly for up to 51 weeks (Tsimikas et al. 2020).  The most advanced 
GalNAc3-conjugated ASO (ISIS 681257; NVS TQJ230) of similar chemistry has entered into a 
large Cardiovascular Outcome Trial (HORIZON, NCT04023552) of 7600 subjects to be treated 
for a median of 4 years at a once-monthly dose of 80 mg every 4-week dosing.  Cumulative 
safety and tolerability data from the platform as well as the preclinical and clinical experience for 
ISIS 678354 are supportive of this dose and dosing frequency (Crooke et al. 2018).  Patients with 
FCS will require chronic treatment and therefore an every 4-week dosing regimen may provide 
advantages over weekly dosing in terms of convenience and compliance for patients. 
2.5. 
Benefit-Risk Assessment 
2.5.1. 
Overall Assessment of Benefit:Risk 
The benefits of treatment of ISIS 678354 are currently unknown.  Due to its mechanism of 
action, ISIS 678354 has the potential to be efficacious for the treatment of patients with FCS. 
No specific risks have been identified with ISIS 678354 in the Phase 1 (678354-CS1) or 
Phase 2 (678354-CS2) studies.  The conjugated nature of ISIS 678354 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 tolerability profile over the parent molecule, ISIS 304801.  Consequently, 
platelet count decreases observed with the much higher doses of the unconjugated parent 
molecule are not anticipated to occur at the dose tested in this study. 
Nevertheless, regular monitoring of platelet counts, liver chemistry, and renal function, and 
stopping rules will be included in the clinical study as described in Section 8.5 and Section 8.6. 
Taking into account the measures implemented to minimize risk to patients participating in this 
study, the potential risks identified in association with ISIS 678354 are justified by the 
anticipated benefits that may be afforded to patients with FCS. 
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 
ISIS 678354.  There may be risks to patients traveling to research sites.  Sites should follow their 


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specific regional guidance (i.e., institutional, local, state, federal, country-level, as applicable) 
with regard to receiving patients for clinical trials.  Visits should continue 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 ISIS 678354. 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled study.  Eligible patients will 
enter an approximately 4-week, but no more than 8-week, Screening Period that includes an at 
least 2-week Diet Stabilization/Run-In Period for patients not already on a stable diet, and an 
approximately 2-week Qualification Period.  Following qualification, approximately 60 eligible 
patients will be randomized 1:1 to Cohort A (50 mg) or Cohort B (80 mg) and each cohort 
further randomized 2:1 to receive ISIS 678354 or placebo in a 53-week Treatment Period.  
Patients in Cohort A will receive 50 mg of ISIS 678354 once every 4 weeks or matching volume 
of placebo (0.5 mL) Weeks 1-49 of the Treatment Period.  Patients in Cohort B will receive 
80 mg ISIS 678354 once every 4 weeks or matching volume of placebo (0.8 mL) Weeks 1-49 of 
the Treatment Period.  Randomization will be stratified by (1) prior history of pancreatitis 
(within 10 years prior to Screening) and (2) previous treatment with volanesorsen.  Dietary 
counseling will commence at the start of the Diet Stabilization Period and will be reinforced at 
intervals throughout the Treatment and Follow-up Period.  Following the Week 53 visit, eligible 
patients may elect to enroll in an open-label extension (OLE) study pending study approval by 
the institutional review board/independent ethics committee (IRB/IEC) and the appropriate 
regulatory authority.  Patients not participating in the OLE will enter the 13-week 
Post-Treatment Evaluation Period.  The primary endpoint for the study will be evaluated after 
the last patient has completed the Week 53/ET visit and will be based on the percent change in 
fasting TG from Baseline at the primary analysis time point (Month 6). 
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. 
3.2. 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3. 
Number of Patients 
Approximately 60 patients are planned to be enrolled in this study. 


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3.4. 
Overall Study Duration and Follow-up 
The study for an individual patient will generally consist of the following periods: 
• An approximately 4-week, but no more than 8-week, Screening Period including a 
Diet Stabilization Period of at least 2 weeks and an approximately 2-week 
Qualification Period (patients on stable diet, for optimal control of TGs and disease 
management, known to the Investigator and followed at the site may go from 
Screening to Qualification without the Diet Run-In Period) 
• A 53-week Treatment Period during which Study Drug will be administered as a once 
every 4-week SC injection (Week 1 through Week 49) 
• A 13-week Post-Treatment Evaluation Period or transition to OLE Study 
Please refer to the Schedule of Procedures in Appendix A. 
3.4.1. 
Screening 
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 outline 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 Period 
The Post-Treatment Follow-up Period is 13 weeks with assessments as outline in the Schedule of 
Procedures in Appendix A. 
Alternatively, following the Week 53 visit, eligible patients may elect to enroll in the OLE study 
pending study approval of this proposed study by the IRB/IEC and the appropriate regulatory 
authority. 
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 expertise in medical 
specialties relevant to the safety of ASO drugs (hematology, hepatology, and nephrology) 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 ISIS 678354, 
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 


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and controlled access to unblinded data are outlined in the DSMB Charter and 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 ICH, 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 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. 
• Remote assessments and at-home visits:  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. 


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• To support Study Drug administration at home, delivery of Study Drug to the 
patient may be undertaken at the discretion of the Investigator, 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. 
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 IEC/IRB 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 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 1 time in order to determine eligibility.  In the event the patient is re-consented and 
re-screened the patient must be given a new screening number.  Screening numbers and patient 
identification numbers, once assigned, will not be re-used. 
4.2. 
Randomization 
Patients will be randomized after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Section 5.1 and Section 5.2.  No 
patient may begin treatment prior to randomization and assignment of a unique patient 
identification number. 
Using an Interactive Response Technology (IRT) system, eligible patients will be randomized 
1:1 to Cohort A or Cohort B and each cohort further randomized 2:1 to receive ISIS 678354 or 
placebo.  Patients will be stratified for: 
• Prior history of pancreatitis within 10 years prior to Screening* vs. no history of 
pancreatitis or no history within 10 years prior to Screening 
• Previous treatment with volanesorsen (Yes vs. No) 
* History of pancreatitis is defined as a recorded diagnosis of acute pancreatitis or hospitalization 
or ER visit for severe abdominal pain consistent with acute pancreatitis and for which no 
alternate diagnosis was made. 
The randomization lists will be prepared by an independent external vendor. 


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4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
4.4. 
Unblinding of Treatment Assignment 
The Sponsor and all patients, monitors, and Study Center personnel related to the study 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 an SAE (as defined in Section 9.3.3), and/or when knowledge 
of the treatment assignment will impact the clinical management of the patient, the Investigator 
will have the ability to unblind the treatment assignment for that patient using the IRT. 
The Sponsor or designee will be informed of the unblinding of a subject 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). 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Appendix A) prior to unblinding, as knowledge of the treatment arm could 
influence subject assessment. 
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. A diagnosis of Familial Chylomicronemia Syndrome (type 1 Hyperlipoproteinemia) by 
documentation of confirmed homozygote, compound heterozygote or double 
heterozygote for loss-of-function mutations in type 1-causing genes (such as LPL, 
GPIHBP1, APOA5, APOC2, GPD1, or LMF1) 
4. Fasting TG ≥ 880 mg/dL (10 mmol/L) at Screening.  If the fasting TG is < 880 mg/dL up 
to 2 additional tests may be performed with any single test used to qualify 


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5. History of pancreatitis (defined as a recorded diagnosis of acute pancreatitis or 
hospitalization or ER visit for severe abdominal pain consistent with acute pancreatitis 
and for which no alternate diagnosis was made) within 10 years prior to Screening.  
Patients without a recorded history of pancreatitis, or no recorded history within 10 years 
prior to Screening, are also eligible but their enrollment will be capped at 35% 
(i.e., ≤ 21 of the 60 planned patients) 
6. Willing to follow a diet comprising ≤ 20g fat per day during the study 
7. Willing to complete all Patient Reported Outcome assessments throughout the study as 
described in Section 6.2.5 
8. Satisfy the following: 
a. Females:  must be non-pregnant and non-lactating and either: 
i. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) 
ii. Post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and FSH levels in the postmenopausal range 
for the laboratory involved) 
iii. Abstinent* or 
iv. If engaged in sexual relations of child-bearing potential, agree to use a highly 
effective contraceptive method (refer to Section 6.3.1) from the time of signing 
the informed consent form until at least 17 weeks after the last dose of Study 
Drug (ISIS 678354 or placebo)  
b. Males:  Surgically sterile, abstinent*, or if engaged in sexual relations with a female 
of childbearing potential, patient is using a highly effective contraceptive method 
(refer to Section 6.3.1) from the time of signing the informed consent form until at 
least 17 weeks after the last dose of Study Drug (ISIS 678354 or placebo) 
* 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 
9. Atypical antipsychotic medications (e.g., olanzapine and clozapine) will be allowed if on 
a stable dose for at least 3 months prior to Screening and dose and regimen expected to 
remain constant through the end of their participation in this study 
10. The following concomitant medications will be allowed if on a stable dose for at least 
4 weeks prior to Screening and dose and regimen expected to remain constant through the 
end of their participation in this study (occasional or intermittent use of over-the-counter 
[OTC] medications will be allowed at Investigator’s discretion): 
a. Statins, omega-3 fatty acids (prescription and OTC), fibrates, or other lipid-lowering 
medications.  Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand through the end of the study 
b. Antidiabetic medications 


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c. Antihypertensive medications 
d. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) and 
regular clinical monitoring is performed 
e. Tamoxifen, estrogens or progestins 
5.2. 
Exclusion Criteria 
1. Clinically significant abnormalities in medical history (e.g., previous acute coronary 
syndrome within 6 months of Screening, major surgery within 3 months of Screening) or 
physical examination 
2. Active pancreatitis within 4 weeks prior to Screening 
3. Screening laboratory results as follows, or any other clinically significant abnormalities 
in screening laboratory values that would render a patient unsuitable for inclusion 
a. Platelet count < 100K/mm3 at Screening or Qualification.  If the platelet count is 
< 100K/mm3 up to 2 additional tests may be performed to qualify at both Screening 
and Qualification. 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3.0 × upper 
limit of normal (ULN) 
c. Total bilirubin > ULN unless due to Gilbert’s syndrome 
d. Estimated GFR < 45 mL/min/1.73 m2 [as determined by the CKD-EPI formula for 
creatinine clearance; (Levey et al. 2009)] 
e. Urine protein/creatinine ratio (UPCR) ≥ 500 mg/g, or urine albumin/creatinine 
(UACR) ratio ≥ 300 mg/g 
4. Uncontrolled arterial hypertension (BP > 160/100 mm Hg) 
5. History of bleeding diathesis or coagulopathy or clinically significant abnormality in 
coagulation parameters at Screening 
6. 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 
7. Active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B 
diagnosed by initial serological testing and confirmed with RNA testing, or prior 
treatment for hepatitis C.  Patients at Screening who test positive by serology, but 
negative by RNA may be allowed in consultation with the Sponsor Medical Monitor 
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated.  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 
9. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 
60 days of Screening 


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10. 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 
11. 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 
12. 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 
b. Plasma apheresis within 4 weeks prior to Screening or planned during the study 
13. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
14. Have any other conditions, which, in the opinion of the Investigator would make the 
patient unsuitable for inclusion, or could interfere with the patient participating in or 
completing the study 
6. 
STUDY PROCEDURES 
6.1. 
Study Schedule  
All required study procedures are outlined in 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 
screening results may be re-tested once for determination of patient eligibility after consultation 
with the Sponsor Medical Monitor.  Patients may be re-screened 1 time in order to determine 
eligibility. 
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 not already on a stable diet will have 2 weeks of diet 
run-in, followed by a qualification visit, during which final eligibility assessments will be 
performed.  Patients on a stable diet, known to the Investigator and followed at the site, may go 
from Screening to qualification without a 2-week diet run-in.  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. 


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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.  Patients will receive Study Drug administered by SC injection once every 
4 weeks for 49 weeks.  Collection and measurement of vital signs, physical examination results, 
ECGs, laboratory parameters (Appendix B), ISIS 678354 plasma concentrations, anti-drug 
antibody (ADA) and biomarker samples, patient reported outcome assessments, AEs and 
concomitant medication/procedure information will be performed according to the Schedule of 
Procedures in Appendix A. 
6.1.3. 
Post-Treatment Period 
After completion of the Week 53 visit assessments, patients will enter the 13-week 
Post-Treatment Follow-up Period.  Alternatively, after completion of the Week 53 visit 
assessments, eligible patients may elect to receive ISIS 678354 in the OLE study, pending study 
approval by the IRB/IEC and the appropriate regulatory authority.  In this case, patients will 
need to sign the IRB/IEC approved informed consent.  Patients who complete Study Visit Week 
53, and meet eligibility requirements, may start the Treatment Period in the OLE study any time 
after the Week 53 visit and, if relevant, discontinue participation in the CS3 Post-Treatment 
Evaluation 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 and 
preferably not more than 12 hours.  Any confirmatory test, or test taken for safety reasons, may 
be taken at any time, irrespective of fasting status, but no later than 7 days after the initial result 
is obtained.  During preparation for fasting samples, the patient can drink water and they should 
ensure that they consume sufficient water in order to not become dehydrated. 
If tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or 
missing, a repeat blood or urine specimen should be re-drawn as soon as possible (ideally within 
1 week). 
While on treatment, hematology samples will be collected at least every 14 days (± 2 days).  In 
the event that a hematology sample is unreportable (e.g., due to hemolyzed or clumped blood 
samples), patient dosing cannot continue until another sample (central or local) is repeated and 
determined not to have met a platelet stopping rule. 
Investigators may, at their discretion, test specific laboratory parameters which may be prone to 
clotting, clumping or hemolysis (e.g., hematology samples) at their 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). 


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If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
While on treatment, blood and urine samples for renal function testing will also be collected 
every 14 days (± 2 days) and sent to the central laboratory for analysis for the first 3 months of 
the study treatment, and monthly thereafter during the Treatment Period per Section 8.5.2. 
While on treatment, liver function testing will also be collected every 14 days (± 2 days) and sent 
to the central laboratory for analysis for the first 3 months of the study treatment, and monthly 
thereafter during the Treatment Period per Section 8.5.1. 
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 the site’s local laboratories are received by the Study Center staff per the local laboratories’ 
standard reporting time, and should be entered as soon as possible (ideally within 1 week) into 
the electronic Case Report Form (eCRF) to inform the Sponsor and CRO study monitoring 
teams. 
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the 
Investigator, or designee, to ensure that the count has not met a dose interruption or stopping 
rule.  Any case of platelet count reduction to levels below 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 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 48 hours 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 platelet, liver, or renal function 
monitoring/stopping rules, are also reviewed promptly by the Sponsor and the CRO Medical 
Monitors who will agree on actions to be taken.  Within 24 hours of receiving an actionable lab 
alert the CRO Medical Monitor will communicate instructions to the Investigator and the study 
personnel by emailing them the Safety Surveillance Form that needs to be completed and signed 
by the Investigator/study personnel and promptly returned to the Sponsor and CRO Medical 
Monitor.  In urgent cases, such as platelets results below 50,000/mm3, or liver or renal test results 
reaching a critical stopping rule, the Investigator must also be contacted by phone. 
Further information on safety monitoring and actions to be taken by the Study Investigator in the 
event of reduced platelet count are provided in Section 8.5.3 and Section 8.6.3. 


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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, BP, pulse rate, respiratory rate and body 
temperature.  Blood pressure and pulse rate will be recorded after the patient has been in a sitting 
position for at least 5 minutes.  Blood pressure should always be measured on the same arm 
(preferentially on the left arm).  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 during the Treatment Period and at each post-treatment follow-up visit as 
outlined in Appendix A. 
Electrocardiography will be recorded after the patient has been resting in a supine position for at 
least 5 minutes.  Electrocardiography will be performed in triplicate. 
6.2.4. 
Pharmacokinetic Sampling 
Blood samples for the determination of plasma ISIS 678354 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 C. 
6.2.5. 
Patient Reported Outcomes Assessments 
All patients are to complete the FCS Symptoms Two Week Recall at Screening and the FCS 
Symptoms and diet questionnaire on a daily basis for FCS symptoms/diet (minimum of 4 daily 
assessments per week) and every 4 weeks for FCS Impacts, and complete the PROMIS Adult 
Short Form v1.1 (Pain Interference 8a) every 4 weeks, for the duration of the study as outlined in 
Appendix A.  Health-related quality of life (as measured by the PROMIS 29+2 Profile vs. 2.1) 
and an optional PROMIS® Short Form v2.0 – Cognitive Function 4a will be assessed at Baseline, 
3 months, 6 months and end of study.  Patient-reported global impression of severity (PGIS) will 
be administered at Baseline and every 4 weeks; the patient-reported global impression of change 
(PGIC) at 6 months and end of study.  Patient-reported global impression of severity and PGIC 
are administered for purposes of PRO validation and estimation of minimal important difference 
(MID). 
6.2.6. 
Pancreatitis Medical History 
Patient records will be reviewed for incidents of acute pancreatitis occurring up to 10 years prior 
to Screening and information relating to these events, occurring up to 5 years prior to Screening, 
will be collected for independent adjudication. 


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6.3. 
Restriction 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 17 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 one of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age 
or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post-hysterectomy 
For the purposes of the study, 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 child-bearing potential uses a highly effective 
contraceptive method (defined below) 
For female patients and female partners of male patients, highly effective female 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). 
†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 who are pregnant must use condoms to ensure that the fetus 
is not exposed to the Study Drug. 


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6.3.2. 
Other Requirements 
All patients will be required to fast for at least 10 hours before visits requiring fasted blood 
sampling. 
All patients will be encouraged to follow a diet comprising 20 g fat per day during the study. 
Alcohol should not be consumed during the study. 
All patients will be given an instruction card that must be presented to the treating physician if a 
suspected case of pancreatitis occurs.  The card will explain that the patient is in a clinical trial 
and that serum lipase and/or amylase measures should be done in order to adjudicate the event 
based on Atlanta Classification (Banks et al. 2013).  If serum lipase and/or amylase activity is 
less than 3 × ULN, imaging, preferably contrast-enhanced computed tomography, should be 
considered to confirm the diagnosis of acute pancreatitis per the Atlanta Criteria. 
7. 
STUDY DRUG 
7.1. 
ISIS 678354 or Placebo 
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. 
Olezarsen 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. 
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. 


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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 for 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 for 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 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. 
8.5. 
Safety Monitoring Rules 
Stopping rules are described below in Section 8.6. 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
• For the purposes of safety monitoring Baseline is defined as the average of the 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 clinical laboratory results meeting any of the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 


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initial measurement) on new specimens.  All new specimen collections should take place as soon 
as possible (ideally within 3 days but no later than 7 days of the initial collection).  For stopping 
rules, if the initial laboratory result is observed during the Treatment Period, the results from the 
retest must be available prior to administering the next dose of Study Drug. 
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 (ISIS 678354 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 appropriately qualified 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 stopping criteria described below (refer to 
Section 8.6.1 through Section 8.6.3) are met, the patient will be permanently discontinued from 
further treatment with Study Drug (ISIS 678354 or placebo), evaluated fully as outlined below 
and in consultation with the Sponsor Medical Monitor or appropriately qualified designee, and 
will be followed up in accordance with Section 8.8 of the protocol. 
The Investigator may interrupt or permanently discontinue study treatment for any medical 
reason including changes in clinical laboratory results. 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline, please refer to 
guidance in Section 8.5 above. 
All patients will have liver chemistry tests monitored every 14 days (± 2 days) for the first 
3 months of the Treatment Period, and monthly thereafter during the Treatment Period.  Upon 
completion of the study Treatment Period, liver chemistry tests should be monitored as per visit 
schedule in Appendix A. 
In the event of appearance of symptoms or signs of hepatic injury (jaundice, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, abnormal bleeding or bruising, or 
eosinophilia > ULN) liver enzymes and bilirubin should be tested as soon as possible (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), the initial measurement(s) should be confirmed as described in 
Section 8.5. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 × ULN (or 
the greater of 2 × baseline value or 3 × ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, alkaline phosphatase [ALP], INR and total bilirubin) retested at 
least once weekly until ALT and AST levels become ≤ 1.2 × ULN or 1.2 × baseline if the 
baseline value was > ULN. 


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Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
• Obtain a more detailed history of symptoms and prior and concurrent diseases 
• Obtain further history for concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets 
• Obtain a history for exposure to environmental chemical agents and travel 
• Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, cytomegalovirus 
(CMV) IgM, and EBV antibody panel) 
• Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach ≥ 5 × ULN. 
The Study Drug must be interrupted until all evaluations and consultation with the Sponsor 
Medical Monitor is complete. 
Patients with confirmed ALT or AST levels > 3 × ULN (or the greater of 2 × baseline value or 
3 × ULN if the baseline value was > ULN) without an alternative explanation, and not meeting 
any of the Stopping Rules for liver chemistry elevations described in Section 8.6.1, must have 
Study Drug dose permanently reduced to 50 mg, if on an 80-mg dose.  Patients on 50 mg should 
remain on the 50-mg dose. 
All routine liver function test results will be reviewed on an ongoing basis at the weekly safety 
review by the Sponsor Medical Monitor. 
All lab alerts for abnormal liver function tests must be promptly reviewed by the Investigator 
(within 48 hours of receipt) and Medical Monitor(s) (within 24 hours of receipt) as described in 
Section 6.2.1. 
Lab alerts for abnormal liver chemistry tests will be issued for:  1) ALT or AST > 3 × ULN; 
2) ALT or AST > 2 × baseline; 3) total bilirubin > ULN; 4) ALP > ULN.  These alert levels are 
set to anticipate the risk of a combined elevation of aminotransferases and bilirubin as per the 
FDA Guidance referenced in Section 8.5.1 above. 
8.5.2. 
Safety Monitoring for Renal Function 
While on treatment, all patients will have renal function tests monitored every 14 days (± 2 days) 
for the first 3 months of the Treatment Period, and monthly thereafter during the Treatment 
Period.  Upon completion of the study Treatment Period, renal function tests should be 
monitored as per visit schedule in Appendix A. 
In the event of appearance of symptoms or signs consistent with renal dysfunction such as 
hematuria, polyuria, anuria, flank pain, new-onset hypertension, nausea and/or anorexia, renal 


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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. 
Renal function surveillance will include serum creatinine and urinalysis including UACR, 
UPCR, urinary red blood cells (RBC).  The assessment of serum creatinine and urinalysis more 
frequently than every 14 days will be guided by consultation with a local nephrologist. 
All renal function test results will be reviewed on an ongoing basis by the Medical Monitor. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.2. 
If any of the below criteria are met, an alert will be issued and treatment with Study Drug should 
immediately be interrupted, and the Study Medical Monitor should be informed.  In addition, the 
result should be confirmed as soon as possible (as described in Section 8.5), but no later than 
7 days after the initial event. 
• eGFR (by CKD-EPI formula) decrease from Baseline > 25% 
• Urine albumin/creatinine ratio (UACR) > 300 mg/g, or > 50% Baseline whichever is 
greater 
• UPCR > 500 mg/g, or > 50% Baseline whichever is greater 
If the confirmatory test is negative (i.e., repeat sample taken with 7 days is within normal limits), 
the patient may continue treatment with Study Drug upon consultation with the Medical Monitor.  
If results from additional testing confirm the initial abnormal lab result, the site will obtain any 
additional lab assessments necessary to determine any alternative etiologies that may account for 
the abnormal result, upon consultation with the Medical Monitor. 
The Investigator should also review the patient’s concomitant medications for potentially 
nephrotoxic agents, and, with the results of these evaluations, review any decision to continue or 
discontinue the patient in consultation with the Medical Monitor.  Any decision taken by the 
Investigator to discontinue Study Drug will be made taken into account all available and relevant 
data.  In addition, the decision to discontinue Study Drug may also be based on lesser changes in 
these parameters observed in isolation or in association with other renal-related abnormalities. 
Further instruction regarding treatment interruption and/or permanent stopping of Study Drug 
can be found in Section 8.6.2. 
8.5.3. 
Safety Monitoring for Platelet Count Results 
All patients will have PLT counts monitored at least every 14 days (± 2 days) for the duration of 
the study Treatment Period, and at all post-treatment follow-up visits, and must not receive Study 
Drug without an interpretable PLT count result in the prior 14 days.  Upon completion of the 
study Treatment Period, PLTs will be monitored at least every 14 days (± 2 days) for the first 
6 weeks and then at 8 and 13 weeks Post-End of Treatment Period (as per visit schedule). 
All PLT count results must be reviewed promptly (within 48 hours of receipt) by the Investigator 
or the designee to ensure that the count has not met 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 
Drug Dose 
Monitoring 
Normal range, ≥ 140K/mm3 No action 
Monitor every 14 days (± 2 days) 
Below values to be 
confirmed ideally within 
3 days but no later than 
7 days 
If PLT count is confirmed, follow 
dosing guidance below: 
If PLT count is confirmed, follow monitoring 
guidance below: 
≥ 100K to < 140K/mm3 
No action 
Monitor every 2 weeks  
≥ 75K to < 100K/mm3 
Discussion with Medical 
Monitor*** 
Closer observation; monitor every week** 
≥ 50K to < 75K/mm3 
Pause dosing.  When ≥ 2 successive 
PLT count values return to 
≥ 100K/mm3 restart dosing only if 
approved by Medical Monitor*** 
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 
˂ 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 recommended**** 
Consider referral to hematologist  
Discontinue anticoagulants/antiplatelet 
agents/NSAIDs medication while PLT count 
˂ 50K/mm3 if possible 
* 
Once a patient commences every 2-week monitoring this frequency of monitoring should continue until the 
platelet count returns to ≥ 140K/mm3) for 2 successive values 
** 
Once a patient commences weekly monitoring this frequency of monitoring should continue until the platelet 
count returns to ≥ 100K/mm3) for 2 successive values. 
*** 
The suitability of the patient for reduced, 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. 
**** Recovery in platelet count may be accelerated by administration of high-dose glucocorticoids.  Treatment as 
recommended by the American Society of Hematology (ASH) (Neunert et al. 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; 
2019). 
 


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Any case of a 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 AESI and should be reported following the same requirements as for SAE 
reporting. 
Table 3: 
Additional Lab Analyses for Patients with Platelet Count Less Than 
50,000/mm3 
The following is a list of lab analyses for patients who have any occurrence of platelet count less 
than 50,000/mm3.  Archived samples prior to Day 1 of investigational treatment may also be 
analyzed in order to determine the patient’s baseline conditions. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes and mean platelet volume 
Total globulins: IgG and IgM 
Complement:  total C3, total C4, C5a 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies 
Anti-ASO antibody 
Note:  These labs may 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 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 an event 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 


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K2EDTA anticoagulated blood will be collected and resulting plasma must be stored allowing 
for a centralized assessment of ISIS 678354 concentrations. 
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 overt bleeding not meeting the criteria for 
MB but that resulted, for example, in medical examination, intervention, or had clinical 
consequences for a patient (Schulman and Kearon 2005). 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epistaxis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
Minor bleeding events are those that do not fulfill the criteria for MB or clinically relevant, 
non-major bleeding events (defined above), for example excess bruising, petechiae, gingival 
bleeding on brushing teeth. 
8.5.5. 
Safety Monitoring for Constitutional Symptoms 
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 that include the acute onset of the following: 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.  


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Patients who experience symptoms of a potential hypersensitivity reaction should be tested 
within 15 minutes to 3 hours after onset of symptoms, or as soon as possible thereafter for: 
• Tryptase 
• High-sensitivity C-reactive protein (hsCRP) 
• Erythrocyte sedimentation rate (ESR) 
• Complement factors (C3, C4, C5a, and Bb) 
• Immunoglobulin E (IgE) 
• CBC with differential 
• Serum chemistry 
• Urinalysis 
• UPCR 
• Anti-drug antibody (ADA) 
• Antinuclear antibody (ANA) 
• Antineutrophilic cytoplasmic antibody (ANCA) 
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 LDL-C Elevations 
Beginning at Week 27, laboratory alerts will be in place to notify the Investigator if a patient has 
an LDL-C > 130 mg/dL (> 100 mg/dL for patients with T2DM or CAD with Baseline 
LDL-C > 100 mg/dL) on 2 consecutive visits.  If this occurs, LDL-C values for this patient will 
be unblinded for the remainder of the study and the Investigator will be encouraged to 
initiate/adjust treatment to lower LDL-C according to country-specific guidelines (e.g., initiate 
statin therapy or increase the statin dose for patients who are already on treatment). 
8.6. 
Stopping Rules 
Monitoring rules are described above in Section 8.5. 
For the purposes of stopping rules, Baseline is defined as the average of the Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations 
All cases of confirmed laboratory results meeting any of the following criteria, but having an 
alternative etiology such as congestive heart failure, introduction of a new drug, some identified 
biliary tract issues etc., must be reviewed by local hepatologist, the DSMB hepatologist, and the 
decision to restart the Study Drug must be made upon reaching a general agreement between 
consulting hepatologist, the DSMB hepatologist, and the Sponsor Medical Monitor that the 
alternative etiology is well supported as the likely cause, and when ALT and AST levels become 


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≤ 3 × ULN.  Until this evaluation is completed and a decision agreed upon, the treatment 
with the Study Drug will remain interrupted. 
In the event of confirmed laboratory results meeting any of the following criteria, and the event 
is without an alternative explanation as discussed with the Medical Monitor, dosing of a 
patient with Study Drug (ISIS 678354 or placebo) will be stopped permanently; values that are 
not confirmed due to failure to retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 × ULN, which is confirmed 
2. ALT or AST > 5 × ULN, which is confirmed and persists for ≥ 2 weeks 
3. 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 
4. 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) 
8.6.2. 
Stopping Rules for Renal Function Test Results 
In the event that the any of the renal monitoring rules summarized in Section 8.5.2 are met, 
treatment with Study Drug should immediately be interrupted and the abnormal result should be 
confirmed as soon as possible, but no later than 7 days after the initial event.  In addition, upon 
consultation with the Medical Monitor, the site will obtain any additional lab assessments 
necessary to determine any alternative etiologies that may account for the abnormal result.  If 
results from additional testing confirm the initial abnormal lab result(s) described in 
Section 8.5.2, and additional evaluations regarding etiology accounting for these abnormalities 
are completed, future treatment of the patient will be determined per the guidelines below: 
• An alternative etiology is identified that may account for abnormal results 
o Patient will have treatment with Study Drug interrupted until either: 
▪ Lab values have returned to baseline, and/or 
▪ Alternative etiology has resolved/recovered, AND 
▪ Study Medical Monitor has approved Study Drug treatment to resume 
• An alternative etiology has not been identified that may account for abnormal results: 
o Patient will be permanently withdrawn from Study Drug treatment 
The follow-up schedule and frequency of renal function monitoring after the initial event will be 
determined by the Medical Monitor in consultation with the Investigator.  The Investigator 
should consider consulting a local nephrologist for any change of renal function that presents a 
concern.  If a renal biopsy is performed, a sample specimen should be made available for 
examination by an independent renal pathologist who has been engaged by the Sponsor to review 
such specimens. 


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8.6.3. 
Stopping Rule for Platelet Count Results 
Actions to be taken in the event of a low PLT count are summarized in Table 2 above. 
8.6.4. 
Stopping Rule for Bleeding Events 
In the event of Major Bleeding or Clinically Relevant Non-major Bleeding (see definitions in 
Section 8.5.4 as assessed by the Investigator, dosing of a patient with Study Drug (ISIS 678354 
or placebo) may be 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). 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
Dose adjustments for platelet 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. 
Dose adjustments should not occur unless absolutely necessary prior to the primary analysis time 
point (Month 6). 
8.8. 
Discontinuation of Study Drug 
A patient must permanently discontinue Study Drug treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of Study 
Drug 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6.1 to Section 8.6.3 
• The patient experiences an AE that necessitates unblinding of the Investigator or 
Sponsor to the patient’s treatment assignment 
The reason for discontinuation of Study Drug must be recorded in the eCRF and source 
documentation. 
8.8.1. 
Follow-up Visits for Early Termination from Treatment Period or 
Post-Treatment Follow-up Period 
Any patient who discontinues early from the Treatment Period should be strongly encouraged to 
attend applicable landmark visits at Weeks 23, 25, 27 and 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.  Any patient who discontinues early from the Post-Treatment 
Follow-up Period should be strongly encouraged to complete follow-up study visits, procedures 
and observations in accordance with Appendix A. 


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Any patient who discontinues early from the Treatment Period or from Post-Treatment 
Follow-up Period should be followed as per the platelet monitoring rules shown in Table 2, 
Section 8.6.3 for the first 6 weeks Post-End of Treatment Period and then at 8 and 13 weeks 
Post-End of Treatment Period (as per visit schedule). 
If a patient discontinues early from the Treatment Period and declines or is unable to participate 
in the above, an ET visit (Week 53 visit assessments) should be performed at the time of 
withdrawal, and ideally within 2 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. 
If the patient discontinues early from the Post-Treatment Follow-up Period and declines or is 
unable to participate in the above, a final visit (assessments from Week 13 of the Post-Treatment 
Follow-up Period) should be performed at the time of withdrawal. 
8.9. 
Withdrawal of Patients from the Study Procedures 
Patients must be withdrawn from study procedures for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
• The patient meets any of the Exclusion Criteria (see Section 5.2) after enrolling in the 
study that in the opinion of the Investigator represents a safety risk to the patient 
Other reasons for withdrawal of patients from study procedures might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the eCRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the early termination study procedures and observations at the time of 
withdrawal Appendix A. 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination of study procedures and observations at the time of withdrawal 
(see Appendix A) and ideally within 2 weeks from the last dose of Study Drug. 
8.10. 
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. 


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8.10.1. 
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 
No GLP-1 agonists, or systemic corticosteroids may be started or adjusted after screening.  
Doses of existing oral anti-diabetic medication, oral contraceptives, hormone replacement 
therapy, oral anticoagulants, antihypertensive medication, or drugs or dietary supplements with 
potential lipid-altering effects should not be adjusted.  Study patients are prohibited from 
receiving other experimental agents during the study.  This includes marketed agents at 
experimental dosages that are being tested for the treatment of hypertriglyceridemia. 
Patients should consult with the Investigator or designee prior to initiating any new medication, 
including non-prescription or herbal compounds or any other non-drug therapy. 
8.10.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
Screening and the end of the Post-Treatment Follow-up Period. 
Disallowed Concomitant Procedures 
Plasma apheresis is not allowed during the study. 
8.11. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded in the eCRF by Study Center 
staff. 
Patients or Study Center Staff will record treatment in a dosing diary that will be reviewed 
periodically by Study Center staff and the Clinical Monitor and entered into the eCRF. 
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. 


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9.2. 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of serious adverse events (SAEs) including SUSARs per the International 
Conference on Harmonization (ICH) guidelines E2A and ICH GCP.  Country-specific regulatory 
requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards/Independent Ethics Committees 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 (ISIS 678354 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 according to local law.  The Sponsor or designee will submit 
SUSARs to Investigators in a blinded fashion. 
The following table identifies the SAEs that the Sponsor or designee will not report on an 
individual basis in an expedited manner because they are anticipated to occur in the study 
population independent of the Study Drug (ISIS 678354 or placebo) exposure.  The Investigator 
still has the responsibility to report all SAEs to the Sponsor as described in Section 9.4.1 to 
Section 9.4.3.5. 
Table 4: 
Expected Event for the Protocol Defined Population by Preferred Term and 
Expected Incidence  
Preferred Term 
Expected Incidence in the Protocol 
Defined Population 
(Gaudet et al. 2010; 2013) 
Pancreatitis associated events including the PTSs of hereditary 
pancreatitis, pancreatitis, pancreatitis acute, pancreatitis 
chronic, pancreatitis necrotizing, pancreatitis relapsing 
0.2–0.35 events per patient year 
 
Fatal pancreatitis associated events will be considered as unexpected and reportable.  The 
Sponsor and DSMB will monitor non-fatal pancreatitis associated SAEs using the incidence rate 
of the event compared to the rate expected in a non-Study Drug exposed population.  If the 
aggregate analysis indicates that an event is occurring more frequently or at a greater severity 
than expected, then the event will be reported. 


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SAEs not specified in the table will be evaluated on a case by case basis to determine whether 
there is a reasonable possibility that the drug caused the event.  If the event is considered by the 
Sponsor or designee to meet the definition of a SUSAR, the event will be reported. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An 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 AE 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) 
• 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 ADRs. 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the AE has been determined by the Sponsor as at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 


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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 
A serious AE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk 
of death.  It does not include an AE or suspected AE 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) 
• Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, 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 AE 
(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 AE 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. 


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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 platelet count < 50,000/mm3 accompanied by a MB event or 
CRNMB event, or platelet 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 within 24 hours of the Study Center’s first knowledge of the event.  The collection of 
SAEs will begin after the patient signs the informed consent form and stop at the end of the 
patient’s Follow-up Period.  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 Follow-Up Serious 
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. 


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9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 678354 or placebo) is characterized by one of 
the following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug, 
e.g., confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug (ISIS 678354 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 
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 (ISIS 678354 or placebo) due to the event is characterized by one 
of the following. 
• None:  No changes were made to Study Drug (ISIS 678354 or placebo) 
administration and dose 


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• 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:  Dosing was temporarily interrupted or 
delayed due to the AE and restarted 
• 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 
• 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 


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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 AE 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 a major adverse 
cardiovascular event (MACE) will be adjudicated by a blinded, independent committee as 
outlined in the MACE Adjudication Charter. 
All AEs and SAEs that occur during the study that are consistent with an event of acute 
pancreatitis will be adjudicated by a blinded, independent committee according to the Atlanta 
classification of acute pancreatitis (Banks et al. 2013) and as outlined in the Pancreatitis 
Adjudication Charter.  In addition, data for 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 report. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 


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9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the patient’s 
consent to participate in the study 
• The condition that required the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the opinion 
of the Investigator between the patient’s consent to participate in the study and the 
timing of the procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3. 
Dosing Errors 
Study Drug (ISIS 678354 or placebo) errors (including overdose, underdose, and administration 
error) should be documented as Protocol Deviations.  A brief description should be provided in 
the deviation, including whether the patient was symptomatic (list symptoms) or asymptomatic, 
and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of Study Drug (ISIS 678354 or placebo) that exceeds protocol specifications and the patient is 
symptomatic, then the symptom(s) should be documented as an AE and be reported per 
Section 9.4. 
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 AE, but 
it may result in an AE.  All AEs associated with an overdose or incorrect administration of Study 
Drug should be recorded on the Adverse Event eCRF.  If the associated AE fulfills seriousness 
criteria, 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 contact the Sponsor or designee 
within 24 hours. 
9.5.4. 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported by designating as ‘Follow-up’ on the 
Pregnancy Forms and reported within 24 hours of awareness of the pregnancy outcome. 


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Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including 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 
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 factors include: 
• Prior history of pancreatitis within 10 years prior to Screening (Yes vs. No) 
• Previous treatment with volanesorsen (Yes vs. No) 
Subgroup analysis for primary endpoint will include, but not limited to, prior history of 
pancreatitis within 10 years prior to Screening (Yes vs. No), previous treatment with 
volanesorsen (Yes vs. No), region (North America, Europe, and ROW), etc., if supported by 
data.  Details of the subgroup analyses will be provided in the SAP. 
In general, the covariate will include stratification factors and baseline measurements (where 
applicable), the details will be provided in Section 10.6.3. 


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10.2. 
Sample Size Considerations 
Based upon prior clinical trial experience with FCS patients, the SD of the percent change from 
Baseline in TGs is approximately 46%.  With 14 patients in each ISIS 678354 treatment group 
and 14 in the pooled placebo group, there would be a 90% power to detect a 60% difference 
between each ISIS 678354 treatment group and pooled placebo group at an alpha level of 0.05 
(two-sided), assuming 60% reduction in the ISIS 678354 treatment patients and no change in the 
placebo patients.  Approximately 60 patients will be enrolled in this trial to account for potential 
early dropouts and to facilitate some general safety evaluations. 
Eligible patients will be randomized 1:1 to Cohort A or Cohort B and each cohort further 
randomized 2:1 (ISIS 678354:placebo) and stratified for: 
• Prior history of pancreatitis within 10 years prior to Screening* vs. no history of 
pancreatitis or no history within 10 years prior to Screening 
• Previous treatment with volanesorsen 
* History of pancreatitis is defined as a recorded diagnosis of acute pancreatitis or hospitalization 
or ER visit for severe abdominal pain consistent with acute pancreatitis and for which no 
alternate diagnosis was made 
10.3. 
Analysis Populations 
Full Analysis Set (FAS):  All patients who are randomized and received any dose of Study Drug 
(ISIS 678354 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. 
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, and who have no major protocol violations 
that could compromise the interpretation of efficacy.  Major violations will be determined prior 
to unblinding for statistical analysis.  This population will be used for supportive inferences 
concerning efficacy. 
Safety Set:  All patients who are randomized and receive any dose of Study Drug.  This 
population will be used for all safety analyses. 
PK Population:  All patients who are randomized and receive at least 1 dose of ISIS 678354, 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 and Primary Time Point 
For platelets, Baseline will be defined as the average of all non-missing pre-dose assessments. 
Baseline for lipid measurements is defined as the average of the pre-dose measurement on Day 1 
and the last measurement closest to Day 1, prior to administration of 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. 


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The primary analysis time point for lipid assessments is defined as the average of Weeks 23, 25, 
and 27 fasting assessments.  If 1 or 2 of the 3 assessments are missing, then non-missing 
assessments will be used. 
10.5. 
Interim Analysis and Multiplicity 
No interim efficacy analysis will be performed. 
To control the overall Type I error rate at 0.05 across the primary endpoints and secondary 
endpoints for the final analysis, the gatekeeping testing strategy will be applied to the primary 
endpoint family and secondary endpoint family.  The hierarchical testing procedure will be 
utilized within the primary endpoint family and secondary endpoint family. 
For the primary endpoint family, the 2 treatment arms will be compared against pooled placebo 
using the hierarchical testing procedure, in which the ISIS 678354 80 mg treatment group will be 
compared to the pooled placebo at the alpha level of 0.05, if the comparison is statistically 
significant (p < 0.05), then the ISIS 678354 50-mg treatment group is compared against the 
pooled placebo at the alpha level of 0.05.  If the comparison of the ISIS 678354 80-mg treatment 
group is not statistically significant, then the comparison of the ISIS 678354 50-mg treatment 
group against pooled placebo and all secondary endpoints will be considered exploratory. 
Testing of secondary endpoint family will be performed only if the comparison of the primary 
endpoint is statistically significant (p < 0.05) for both ISIS 678354 80-mg and 50-mg treatment 
groups.  Testing of the secondary endpoint family will be conducted according to the following 
sequence: 
• Secondary endpoint:  comparison of percent change in fasting TG from Baseline to 
Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in the 
FAS 
• Secondary endpoint:  comparison of percent change in fasting apoC-III from Baseline 
to the primary analysis time point between ISIS 678354 80-mg treatment group and 
pooled placebo in FAS 
• Secondary endpoint:  comparison of percent change in fasting apoC-III from Baseline 
to Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in FAS 
• Secondary endpoint:  comparison of proportion of patients who achieve 
≥ 40% reduction in fasting TG from Baseline to the primary analysis time point 
between ISIS 678354 80-mg treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of percent change in fasting apoB-48 from Baseline 
to the primary analysis time point between ISIS 678354 80-mg treatment group and 
pooled placebo in the FAS 
• Secondary endpoint:  comparison of percent change in fasting non-HDL-C from 
Baseline to the primary analysis time point between ISIS 678354 80-mg treatment 
group and pooled placebo in FAS 


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• Secondary endpoint:  comparison of percent change in fasting TG from Baseline to 
Month 12 between ISIS 678354 50-mg treatment group and pooled placebo in the 
FAS 
• Secondary endpoint:  comparison of percent change in fasting apoC-III from Baseline 
to the primary analysis time point between ISIS 678354 50-mg treatment group and 
pooled placebo in FAS 
• Secondary endpoint:  comparison of percent change in fasting apoC-III from Baseline 
to Month 12 between ISIS 678354 50-mg treatment group and pooled placebo in FAS 
• Secondary endpoint:  comparison of proportion of patients who achieve ≥ 40% 
reduction in fasting TG from Baseline to the primary analysis time point between 
ISIS 678354 50-mg treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of percent change in fasting apoB-48 from Baseline 
to the primary analysis time point between ISIS 678354 50-mg treatment group and 
pooled placebo in the FAS 
• Secondary endpoint:  comparison of percent change in fasting non-HDL-C from 
Baseline to the primary analysis time point between ISIS 678354 50-mg treatment 
group and pooled placebo in FAS 
• Secondary endpoint:  comparison of adjudicated acute pancreatitis event rate during 
the Treatment Period (Week 1 through Week 53/ET) between pooled ISIS 678354 
treatment group and pooled placebo in the subset of FAS with a prior history of 
pancreatitis within 10 years prior to Screening 
• Secondary endpoint:  comparison of adjudicated acute pancreatitis event rate during 
the Treatment Period (Week 1 through Week 53/ET) between pooled ISIS 678354 
treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of adjudicated acute pancreatitis event rate from 
Week 13 to Week 53 between pooled ISIS 678354 treatment group and pooled 
placebo in the subset of FAS with a prior history of pancreatitis within 10 years prior 
to Screening 
• Secondary endpoint:  comparison of adjudicated acute pancreatitis event rate from 
Week 13 to Week 53 between pooled ISIS 678354 treatment group and pooled 
placebo in the FAS 
• Secondary endpoint:  comparison of proportion of patients who achieve 
≥ 70% reduction in fasting TG from Baseline to the primary analysis time point 
between ISIS 678354 80-mg treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of percent change in fasting non-HDL-C from 
Baseline to Month 12 between ISIS 678354 80-mg treatment group and pooled 
placebo in FAS 
• Secondary endpoint:  comparison of percent change in fasting apoB-48 from Baseline 
to Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in FAS 


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• Secondary endpoint:  comparison of proportion of patients who achieve fasting 
TG ≤ 880 mg/dL at the primary analysis time point between ISIS 678354 80-mg 
treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of proportion of patients who achieve 
≥ 70% reduction in fasting TG from Baseline to the primary analysis time point 
between ISIS 678354 50-mg treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of percent change in fasting non-HDL-C from 
Baseline to Month 12 between ISIS 678354 50-mg treatment group and pooled 
placebo in FAS 
• Secondary endpoint:  comparison of percent change in fasting apoB-48 from Baseline 
to Month 12 between ISIS 678354 50-mg treatment group and pooled placebo in FAS 
• Secondary endpoint:  comparison of proportion of patients who achieve fasting 
TG ≤ 880 mg/dL at the primary analysis time point between ISIS 678354 50-mg 
treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of adjudicated acute pancreatitis event rate during 
the Treatment Period (Week 1 through Week 53/ET) between pooled ISIS 678354 
treatment group and pooled placebo in the subset of FAS with ≥ 2 events of 
adjudicated acute pancreatitis in 5 years prior to enrollment 
• Secondary endpoint:  comparison of adjudicated acute pancreatitis event rate from 
Week 13 to Week 53 between pooled ISIS 678354 treatment group and pooled 
placebo in the subset of FAS with ≥ 2 events of adjudicated acute pancreatitis in 
5 years prior to enrollment 
• Secondary endpoint:  comparison of proportion of patients who achieve fasting 
TG ≤ 500 mg/dL at the primary analysis time point between ISIS 678354 
80-mg treatment group and pooled placebo in the FAS 
• Secondary endpoint:  comparison of proportion of patients who achieve fasting 
TG ≤ 500 mg/dL at the primary analysis time point between ISIS 678354 50-mg 
treatment group and pooled placebo in the FAS 
If the comparison of the first secondary endpoint is statistically significant (p < 0.05), then the 
second secondary endpoint will be tested.  However, if the comparison of the first secondary 
endpoint is not statistically significant, then all endpoints of lower rank will be considered 
exploratory.  This process is repeated with each subsequent secondary endpoint. 
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. 


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The primary endpoint will be assessed on the FAS and PPS, with the former being the basis for 
the primary efficacy analysis.  The secondary endpoints will be assessed in the FAS.  All safety 
assessments will be performed on the Safety Set. 
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 (ISIS 678354 or placebo) received will be 
summarized by treatment group.  Patient incidence rates of all AEs will be tabulated by 
MedDRA system organ class, and by MedDRA term.  Tables and/or narratives of treatment 
emergent deaths, serious and significant AEs, including early withdrawals due to AEs, will also 
be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug (ISIS 678354 or placebo) will be summarized. 
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 
the primary analysis time point in fasting TG between each ISIS 678354 treatment group 
vs. pooled placebo using an ANCOVA model in the FAS.  The ANCOVA model will include the 
effects of treatment (ISIS 678354 80 mg, ISIS 678354 50 mg, or Placebo), 2 randomization 
stratification factors (history of pancreatitis and previous treatment with volanesorsen), and 
log-transformed baseline TG.  To account for potential heterogeneity in variance, the 95% CI of 
the treatment differences will be calculated using the robust variance estimator based on the Bell 
and McCaffrey method (Imbens and Kolesár 2016).  If patients have intercurrent event(s) before 
Week 23, 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 and utilized in the primary 
analysis.  Patients with a missing TG value after discontinuation will have TG value multiply 
imputed at Primary analysis time point based on the known assessments from the retrieved 
dropouts (i.e., patients who discontinue before Week 23 but still have TG assessments at 


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Week 23, 25 or 27), if there is a sufficient number of retrieved dropouts.  The imputation model 
will include the following variables:  TG values at baseline and post-baseline visits and the 
2 randomization stratification factors.  The multiple imputation will be stratified by treatment 
group.  If there is not a sufficient number of retrieved dropouts, missing TG value at the primary 
time point will be imputed using a “wash-out” (Jump to Reference, J2R) multiple imputation 
approach.  With the approach, patients treated with ISIS 678354 who discontinue study will have 
missing post-discontinuation TG values multiply imputed based on the fasting TG at Baseline, 
2 randomization stratification factors, and the imputation model for the placebo group.  Patients 
in the placebo group who discontinue the study will have missing post-discontinuation TG 
values multiply imputed based on fasting TG values at Baseline and post-baseline visits from the 
placebo group. 
It is anticipated that the rate of missing data is low. 
The null hypothesis of the primary analysis is that the percent change from Baseline to primary 
analysis time point in fasting TG is the same between each ISIS 678354 and placebo treatment 
groups.  The alternative hypothesis is that the percent change from Baseline to primary analysis 
time point in fasting TG is different between each ISIS 678354 and placebo treatment groups. 
The primary efficacy analysis will take place after the last patient has completed the Week 53/ET 
visit and the database has been locked, and will be based on the percent change from Baseline in 
fasting TG at primary analysis time point (end of Month 6).  Details of the controlled access to 
the unblinded data will be outlined in the SAP and Unblinding Plan. 
During the database lock cleaning process, redacted source documentation may need to be shared 
securely with the site Clinical Research Associate (CRA) for source data verification procedures 
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 the baseline and primary analysis time point. 
• Additional sensitivity analyses using controlled imputations (pattern mixture models) 
with ANCOVA will be conducted in the FAS to assess the robustness of the primary 
analysis results. 
o For patients treated with ISIS 678354 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 withdrawal 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. 


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o All patients treated with ISIS 678354 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 based on the distribution of the placebo group. 
• A nonparametric Wilcoxon rank-sum test will be performed on the percent change in 
fasting TG from baseline to the primary analysis time point in the FAS.  Missing data 
will be handled using the same multiple imputation method as the primary analysis. 
• An additional sensitivity analysis using the two-dimensional tipping-point approach 
will be conducted in the FAS to assess the impact of missing data on the result of the 
primary analysis.  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. 
• An ANCOVA model will be performed in the FAS using the nature log transformed 
data. Missing data will be handled using the same multiple imputation method as the 
primary analysis. 
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 the primary analysis of the primary endpoint. 
• The proportion of patients who achieve ≥ 40% reduction in fasting TG from Baseline 
to the primary analysis time point in the FAS will be compared between each 
ISIS 678354 treatment group and placebo group using a logistic regression model 
with the treatment group, history of pancreatitis (yes/no), previous treatment with 
volanesorsen (yes/no) as the factors, 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.  A sensitivity analysis will be conducted in 
the FAS, in which all patients who have missing data and discontinue treatment 
before Week 23 will be considered as non-responders. 
• The percent change in fasting apoC-III, apoB-48, and non-HDL-C from Baseline to 
the primary analysis time point and Month 12 in the FAS will be analyzed in the same 
way as the primary analysis of the primary endpoint. 
• The proportion of patients who achieve fasting TG ≤ 880 mg/dL at the primary 
analysis time point will be analyzed in the same way as the proportion of patients 
who achieve ≥ 40% reduction in fasting TG.  Missing values will be imputed using 
the same multiple imputation method as the primary analysis of the primary endpoint.  
It will be conducted in the subset of FAS with baseline TG > 880 mg/dL.  
A sensitivity analysis will be conducted in the subset of FAS with baseline 
TG > 880 mg/dL, in which all patients who have missing data and discontinue 
treatment before Week 23 will be considered as non-responders. 
• The following adjudicated acute pancreatitis event rates 
− During the Treatment Period (Week 1 through Week 53) in the subset of FAS 
with a prior history of pancreatitis within 10 years prior to Screening 


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− During the Treatment Period (Week 1 through Week 53) in the FAS 
− From Week 13 to Week 53 in the subset of FAS with a prior history of 
pancreatitis within 10 years prior to Screening 
− From Week 13 to Week 53 in the FAS 
− During the Treatment Period (Week 1 through Week 53) in the subset of FAS 
with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment 
− From Week 13 to Week 53 in the subset of FAS with ≥ 2 events of adjudicated 
acute pancreatitis in 5 years prior to enrollment 
will be compared between pooled ISIS 678354 treatment group and placebo group 
using a Poisson regression model or Negative Binomial regression model with the 
treatment group, history of pancreatitis (yes/no), previous treatment with 
volanesorsen (yes/no) 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 corresponding analysis period (Week 13 to 
Week 53 or Week 1 to Week 53/ET) will be used as an offset variable. 
• The proportion of patients who achieve ≥ 70% reduction in fasting TG from Baseline 
to the primary analysis time point in the FAS will be analyzed in the same way as the 
proportion of patients who achieve ≥ 40% reduction in fasting TG.  Missing values 
will be imputed using the same multiple imputation method as the primary analysis of 
the primary endpoint.  A sensitivity analysis will be conducted in the FAS, in which 
all patients who have missing data and discontinue treatment before Week 23 will be 
considered as non-responders. 
• The proportion of patients who achieve fasting TG ≤ 500 mg/dL at the primary 
analysis time point will be analyzed in the same way as the proportion of patients 
who achieve ≥ 40% reduction in fasting TG.  Missing values will be imputed using 
the same multiple imputation method as the primary analysis of the primary endpoint.  
It will be conducted in the subset of FAS with baseline TG > 500 mg/dL.  
A sensitivity analysis will be conducted in the subset of FAS with baseline 
TG > 500 mg/dL, in which all patients who have missing data and discontinue 
treatment before Week 23 will be considered as non-responders. 
10.6.4. 
Pharmacokinetic and Anti-Drug Antibody Analysis 
Pharmacokinetic analysis will include the following: 
• Determine trough (pre-dose) and post-treatment ISIS 678354 plasma concentrations 
in all patients who receive Study Drug.  For all patients who receive ISIS 678354 
treatment, trough (pre-dose) and peak (2-hr post-treatment ISIS 678354) plasma 
concentrations 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 ISIS 678354 treatment and not participating in the OLE, the 
plasma disposition half-life associated with the apparent terminal elimination phase 
will be calculated using a non-compartment method, if appropriate, using available 


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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 analysis will include the following: 
• Evaluate immunogenicity (IM) (confirmed positive/negative and, when applicable, 
titer of anti-ISIS 678354 antibodies) before, during, and after treatment with 
Study Drug (ISIS 678354 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-ISIS 678354 antibody status may be further 
classified (when applicable) as being either ‘persistent’, ‘transient’, or not 
determinable. 
• Determine subject level IM parameters, which will include but may not 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. 
10.6.5. 
Additional/Exploratory Analyses 
The percent change in fasting TG, fasting apoC-III, fasting apoB-48, and fasting non-HDL-C 
from Baseline to Month 3 (average of Week 13 and Week 17), proportion of patients who 
achieve ≥ 40% reduction or ≥ 70% reduction in fasting TG at Month 3 and Month 12, and 
proportion of patients who achieve fasting TG ≤ 880 mg/dL and ≤ 500 mg/dL at Month 3 and 
Month 12 will also be evaluated. 
The frequency and severity of patient-reported abdominal pain and other FCS-related symptoms, 
diet, and impacts, HRQoL, cognitive function, (Appendix E) and ER visits, incidence of 
all-cause hospitalizations and total inpatient days will be compared between ISIS 678354 and 
placebo groups. 
Details of the analyses will be provided in the SAP. 


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11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor 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 (ISIS 678354 or placebo) are 
administered. 
Importantly, patients should be informed of the possibility and risks of a reduction in platelet 
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. 
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 Good Clinical Practice (GCP) 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 
Study Center or 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. 


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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. 
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 or designee reserves the right to terminate the study.  The Investigator reserves the 
right to terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor or designee should notify the IEC/IRB in writing of the trial’s completion 
or early termination and send a copy of the notification to the Sponsor or designee. 


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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 
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, 


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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. 
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. 
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Experience.” Nucleic Acid Ther 29 (1): 16–32 
Davidson et al.  2017.  “The Burden of Familial Chylomicronemia Syndrome: Interim Results 
from the IN-FOCUS Study.” Expert Rev Cardiovasc Ther 15 (5): 415–23 
Davidson et al.  2018.  “The Burden of Familial Chylomicronemia Syndrome: Results from the 
Global IN-FOCUS Study.” J Clin Lipidol 12 (4): 898-907.e2 
Doolittle et al.  2009.  “Lipase Maturation Factor LMF1, Membrane Topology and Interaction 
with Lipase Proteins in the Endoplasmic Reticulum.” J Biol Chem 284 (48): 33623–33 
FDA  2005.  “Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers” 


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Fox et al.  2020.  “PROMIS® and Neuro-QoLTM Measures Are Valid Measures of Health-
Related Quality of Life among Patients with Familial Chylomicronemia Syndrome.” Expert 
Review of Cardiovascular Therapy 18 (4): 1–8 
Gaudet et al.  2015.  “Antisense Inhibition of Apolipoprotein C-III in Patients with 
Hypertriglyceridemia.” N Engl J Med 373 (5): 438–47 
Gaudet et al.  2014.  “Targeting APOC3 in the Familial Chylomicronemia Syndrome.” N Engl J 
Med 371 (23): 2200–2206 
Gaudet et al.  2013.  “Efficacy and Long-Term Safety of Alipogene Tiparvovec (AAV1-
LPLS447X) Gene Therapy for Lipoprotein Lipase Deficiency: An Open-Label Trial.” Gene Ther 
20 (4): 361–69 
Gaudet et al.  2010.  “Review of the Clinical Development of Alipogene Tiparvovec Gene 
Therapy for Lipoprotein Lipase Deficiency.” Atheroscler Suppl 11 (1): 55–60 
Geary et al.  1997.  “Antisense Oligonucleotide Inhibitors for the Treatment of Cancer: 1. 
Pharmacokinetic Properties of Phosphorothioate Oligodeoxynucleotides.” Anticancer Drug Des 
12: 383–93 
Geary et al.  2003.  “Pharmacokinetics of a Tumor Necrosis Factor-α Phosphorothioate 2′-O-(2-
Methoxyethyl Modified Antisense Oligonucleotide: Comparison Across Species.” Drug 
Metabolism and Disposition 31 (11): 1419–28 
Gelrud et al.  2017.  “The Burden of Familial Chylomicronemia Syndrome from the Patients’ 
Perspective.” Expert Review of Cardiovascular Therapy 15 (11): 879–87 
Gordts et al.  2016.  “ApoC-III Inhibits Clearance of Triglyceride-Rich Lipoproteins through 
LDL Family Receptors.” J Clin Invest 126 (8): 2855–66 
Graham et al.  2013.  “Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces 
Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans.” Circ Res 112 (11): 1479–
90 
Henry et al.  2000.  “Chemically Modified Oligonucleotides Exhibit Decreased Immune 
Stimulation in Mice.” J Pharmacol Exp Ther 292: 468–79 
Imbens and Kolesár  2016.  “Robust Standard Errors in Small Samples: Some Practical Advice.” 
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Inoue et al.  1987.  “Sequence‐dependent Hydrolysis of RNA Using Modified Oligonucleotide 
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Iqbal et al.  2020.  “Managing Hyperlipidaemia in Patients with COVID-19 and during Its 
Pandemic: An Expert Panel Position Statement from HEART UK.” Atherosclerosis 313: 126–36 
Ito et al.  1990.  “Hypertriglyceridemia as a Result of Human Apo CIII Gene Expression in 
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Jacobson et al.  2015.  “National Lipid Association Recommendations for Patient-Centered 
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Kim et al.  2014.  “Antisense Oligonucleotides on Neurobehavior, Respiratory, and 
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69 (1): 49–60 


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Kinnunen and Ehnolm  1976.  “Effect of Serum and C-Apoproteins from Very Low Density 
Lipoproteins on Human Postheparin Plasma Hepatic Lipase.” FEBS Lett 65: 354–57 
Lemieux et al.  2003.  “Contribution of Apo CIII Reduction to the Greater Effect of 12-Week 
Micronized Fenofibrate than Atorvastatin Therapy on Triglyceride Levels and LDL Size in 
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Levey et al.  2009.  “Proteinuria as a Surrogate Outcome in CKD: Report of a Scientific 
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Mann et al.  1997.  “Inhibitory Effects of Specific Apolipoprotein C-III Isoforms on the Binding 
of Triglyceride-Rich Lipoproteins to the Lipolysis-Stimulated Receptor.” J Biol Chem 272 (50): 
31348–54 
McKay et al.  1999.  “Characterization of a Potent and Specific Class of Antisense 
Oligonucleotide Inhibitor of Human Protein Kinase C-α Expression*.” Journal of Biological 
Chemistry 274 (3): 1715–22 
Mendivil et al.  2010.  “Metabolism of Very-Low-Density Lipoprotein and Low-Density 
Lipoprotein Containing Apolipoprotein C-III and Not Other Small Apolipoproteins.” 
Arterioscler Thromb Vasc Biol 30 (2): 239–45 
Monia et al.  1993.  “Evaluation of 2’-Modified Oligonucleotides Containing 2’-Deoxy Gaps as 
Antisense Inhibitors of Gene Expression.” J Biol Chem 268: 14514–22 
Neunert et al.  2019.  “American Society of Hematology 2019 Guidelines for Immune 
Thrombocytopenia.” Blood Adv 3 (23): 3829–66 
Petersen et al.  2010.  “Apolipoprotein C3 Gene Variants in Nonalcoholic Fatty Liver Disease.” 
N Engl J Med 362 (12): 1082–89 
Pollin et al.  2008.  “A Null Mutation in Human APOC3 Confers a Favorable Plasma Lipid 
Profile and Apparent Cardioprotection.” Science 322 (5908): 1702–5 
Prakash et al.  2014.  “Targeted Delivery of Antisense Oligonucleotides to Hepatocytes Using 
Triantennary N-Acetyl Galactosamine Improves Potency 10-Fold in Mice.” Nucleic Acids 
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Provan et al.  2019.  “Updated International Consensus Report on the Investigation and 
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Primary Immune Thrombocytopenia.” Blood 115 (2): 168–86 
Schaap et al.  2004.  “ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density 
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Scherer et al.  2014.  “Issues in Hypertriglyceridemic Pancreatitis: An Update.” J Clin 
Gastroenterol 48 (3): 195–203 
Schulman and Kearon  2005.  “Definition of Major Bleeding in Clinical Investigations of 
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Haemostasis 3 (4): 692–94 


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Schuster et al.  2011.  “Identification of Mutations in the Lipoprotein Lipase (LPL) and 
Apolipoprotein C-II (APOC2) Genes Using Denaturing High Performance Liquid 
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Stockert  1995.  “The Asialoglycoprotein Receptor: Relationships between Structure, Function, 
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Surendran et al.  2012.  “Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in Patients 
with Severe Hypertriglyceridaemia.” J Intern Med 272 (2): 185–96 
Tremblay et al.  2011.  “Etiology and Risk of Lactescent Plasma and Severe 
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Tsimikas et al.  2020.  “Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.” New 
England Journal of Medicine 382 (3): 244–55 
Valdivielso et al.  2014.  “Current Knowledge of Hypertriglyceridemic Pancreatitis.” European 
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Injury of Isolated Acinar Cells and Pancreatitis Model in Lipoprotein Lipase-Deficient Mice.” 
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Yu et al.  2015.  “Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse 
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(22): 4684–92 
  


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14. 
APPENDICES 
 


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APPENDIX A. SCHEDULE OF PROCEDURES 
 
 


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Appendix A Schedule of Procedures 
 
Screening 
Treatment Period 
Follow-up Period 
Run-inA Qual 
Study Week 
-4 to -2 -2 to 
-1O 
1 
5 O 9O 13O 17O 21O 23/ET
-L1O,R 
25/ET
-L2O,R 
27/ET
-L3O,R 29O 33O 37O 41O 45O 49O 51/ET
-L4O,R 
53/ET-
L5 O, R or 
Tx ETO 
4O, P 8O, P 
13O, P /  
Post-
Tx ET  
Study Day 
-28 to  
-15 
-14 to  
-7 
1 
29 57 85 113 141 156 
169 
183 
197 225 253 281 309 337 351 
365 
28P 
56P 
91P 
Visit and Testing Window ± Days 0 
0 
-3B 2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical HistoryC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic testingS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and HeightE 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Vital Signs 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Physical Examination 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12-lead ECG (triplicate) 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Pregnancy TestF 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Extended UrinalysisG 
X 
 
EVERY 14 DAYS 
(± 2 days)O 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Serum Creatinine H, J 
X 
 
EVERY 14 DAYS 
(± 2 days)O 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Chemistry PanelI, J 
X 
 
EVERY 14 DAYS 
(± 2 days)O 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
HematologyJ 
X 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS (± 2 days)O 
X 
Coagulation (aPTT, PT, INR) 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Lipid PanelI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
HbA1c, HOMA-IR, Fructosamine, 
Glycated Albumin 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
hsCRP 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-drug Antibody 
 
 
XO, Q 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Plasma PK - ISIS 678354K 
 
 
XO, Q 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 


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Appendix A Schedule of Procedures (Continued) 
 
Screening 
Treatment Period 
Follow-up Period 
Run-inA Qual 
Study Week 
-4 to -2 -2 to 
-1O 
1 
5 O 9O 13O 17O 21O 23/ET
-L1O,R 
25/ET
-L2O,R 
27/ET
-L3O,R 29O 33O 37O 41O 45O 49O 51/ET
-L4O,R 
53/ ET-
L5 O, R or 
Tx ETO 
4O, P 8O, P 
13O, P / 
Post-
Tx ET 
Study Day 
-28 to  
-15 
-14 to  
-7 
1 
29 57 85 113 141 156 
169 
183 
197 225 253 281 309 337 351 
365 
28P 
56P 
91P 
Visit and Testing Window ± Days 0 
0 
-3B 2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Archived Serum & Plasma  
SamplesI, L 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
FCS Symptoms Two Week Recall 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FCS Symptoms and Diet 
DAILY DIARY 
FCS Impacts; Pain Interference 
Short Form 8a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Global Impression of 
Severity (PGIS) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Patient Global Impression of 
Change (PGIC) 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Health-related Quality of Life 
(PROMIS 29+2 Profile v2.1).  
PROMIS Cognitive Function 4a 
(optional) 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Assessment of ER Visits, 
Hospitalization and Inpatient Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet/Alcohol CounselingM 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Study Drug:  SC InjectionN 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
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, but no more than 8 week, Screening Period that includes an at least 2-week Diet Stabilization/Run-In 
Period for patients not already on a stable diet.  Patients on stable diet, for optimal control of TGs and disease management, known to the Investigator and 
followed at the site may go from Screening to qualification without the Diet Run-In 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 Patient charts will be reviewed in order to collect disease associated medical history data 


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Appendix A 
Schedule of Procedures (Continued) 
D For confirmation of menopause at Screening per inclusion criteria  
E Height only required at Screening 
F 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, including qualification 
G 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. 
H Serum Creatinine will be collected as a part of chemistry panel 
I Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours, unless tests are repeated for Safety reasons 
J If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen should be re-drawn as soon as possible (ideally within 3 days and not later than 7 days).  All platelet count results will be reviewed promptly (within 
48 hours of receipt) by the Investigator.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor 
K Refer to Appendix C for PK Sampling schedule 
L Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or 
chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) and will be retained until at least completion of the 
final study report 
M Recommended time points for qualified site personnel to reinforce compliance to diet and alcohol restrictions  
N Cohort A:  Patients to receive 50-mg Study Drug once every 4 weeks for Weeks 1-49.  Cohort B:  Patients to receive 80-mg Study Drug once every 4 weeks for 
Weeks 1-49 
O Assessments and procedures to be conducted by either the Study Center or a Home Healthcare service (if available) as arranged by the Study Center personnel.  
Physical Exam will be Body Assessment if conducted by a Home Healthcare professional 
P Weeks/Days from end of treatment.  End of treatment is defined as 1 dosing interval post-last dose 
Q To be conducted on Study Days 1, 15, and 29 (each ± 2 days) 
R Landmark visit.  For early termination landmark (ET-L) visits:  Week 23 is ET-L1, Week 25 is ET-L2, Week 27 is ET-L3, Week 51 is ET-L4, and Week 53 is 
ET-L5 
S Redacted historical FCS genetic result reports may be collected by the Sponsor for review along with the current genetic testing 
 
 


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APPENDIX B. LIST OF LABORATORY ANALYTES 
 
 


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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 ISIS 678354 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) 
 
Coagulation 
• aPTT 
• PT 
• INR 
 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
• HDL cholesterol 
• ApoB 
• ApoB-48 
• Chylomicron-TG 
• Triglycerides 
• VLDL 
• ApoC-III 
• Non-HDL-C 
• ApoA-1 
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 
• ISIS 678354 (total full 
length ASO) 
concentration in plasma 
 
Immunogenicity 
• Anti-ISIS 678354 
antibodies 
 
Other assessments 
• HbA1c 
• HOMA-IR 
• Fructosamine 
• Glycated albumin 
Inflammatory 
• hs-CRP  
 
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)  
1  Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, IM or to assess other actions of ISIS 678354 with plasma 
constituents 
 
 


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APPENDIX C. PHARMACOKINETIC SAMPLING SCHEDULE 
 
 


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Appendix C PK Sampling Schedule 
Blood samples for the determination of plasma ISIS 678354 concentrations will be collected prior to dosing, and at various time points 
throughout the Dosing and Post-Treatment Follow-up Period as noted in the table below.  Plasma PK 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 ISIS 678354 with plasma constituents. 
Plasma Trough and Post-Treatment Sampling Schedule for all Patients 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
3 
5 
9 
13 
17 
21 
25/ET-
L2* 
29 
37 
45 
53/ET-
L5* or 
Tx ET 
4** 
8** 
13/Post 
Tx ET** 
Study 
Day 
1 
15 
29 
57 
85 
113 141 
169 
197 
253 
309 365 
28** 56** 
91** 
 
Pre-dose, 
2 hr ± 15 min***, 
and 4 hr ± 30 min*** 
Any 
time  
Pre-
dose 
Pre-
dose 
Pre-dose 
and 2 hr ± 
15 min 
Pre-
dose 
Pre-
dose 
Pre-dose 
and 2 hr ± 
15 min 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Any 
time 
Any 
time 
Any 
time 
Any time 
* Landmark visit.  For early termination landmark (ET-L) visits:  Week 25 is ET-L2 and Week 53 is ET-L5 
** Weeks/days from end of treatment.  End of treatment is defined as 1 dosing interval post-last dose 
*** Samples can be collected within the ± 15 min and ± 30 min window, but the actual sampling time should be recorded accurately in eCRF 
 
 
 


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APPENDIX D. 
GRADING SCALE FOR ADVERSE EVENTS 
RELATING TO LABORATORY ABNORMALITIES 
 
 


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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for 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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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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APPENDIX E. PATIENT REPORTED OUTCOME ASSESSMENTS 
 
Familial Chylomicronemia Syndrome (FCS) - Symptoms and Impacts  
Familial Chylomicronemia Syndrome (FCS) – Symptoms (Two Week Recall) 
FCS Diet Questions for Daily Diary 
PROMIS® Item Bank v1.1 – Pain Interference – Short Form 8a 
PROMIS® 29+2 Profile v.2.1 (PROPr) 
PROMIS®  Short Form v2.0 – Cognitive Function 4a 
Patient Global Impression of Severity (PGIS) Scale 
Patient Global Impression of Change (PGIC) Scale 
 


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Familial Chylomicronemia Syndrome (FCS)- Symptoms (Two week Recall) 
Symptoms 
1. How would you rate your worst abdominal pain in the past 2 weeks? 
 
□ 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
7 
□ 
8 
□ 
9 
□ 
10 
 
No 
abdominal 
pain 
 
 
 
 
 
 
 
 
 
Worst 
possible 
abdominal 
pain 
2. How would you rate your physical fatigue in the past 2 weeks? 
 
□ 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
7 
□ 
8 
□ 
9 
□ 
10 
 
No 
physical 
fatigue 
 
 
 
 
 
 
 
 
 
Worst 
possible 
physical 
fatigue 
 
3. How would you rate your difficulty thinking in the past 2 weeks? 
 
□ 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
7 
□ 
8 
□ 
9 
□ 
10 
 
No 
difficulty 
thinking 
 
 
 
 
 
 
 
 
 
Worst 
possible 
difficulty 
thinking 
4. How would you rate your diarrhea in the past 2 weeks? 
 
□ 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
7 
□ 
8 
□ 
9 
□ 
10 
 
No 
diarrhea 
 
 
 
 
 
 
 
 
 
Worst 
possible 
diarrhea 
 
 
 
 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
102 
FCS Diet Questions for Daily Diary 
 
Did you fast (not eat) in the past 24 hours? (select one) 
o I completely fasted and did not eat 
o I partially fasted and ate less than I normally would 
o I did not fast and ate as I normally do 
If endorse item 2 or 3, follow up with: 
How would you describe your dietary fat intake in the past 24 hours? (select one) 
o I have eaten less than 10g of fat 
o I have eaten 10 – 20g of fat 
o I have eaten more than 20g of fat 
 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
103 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
104 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
105 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
106 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
107 
 


ISIS 678354-CS3 
CONFIDENTIAL 
Amendment 9
Protocol  
2 August 2023
 
108 
 


Version: 1
Version Date: 04 Aug 2023
Title: 678354-CS3 Protocol Amendment 9: A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study of AKCEA-APOCIII-LRx (ISIS 678354) Administered
Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS)
 Clinical Development 
04-Aug-2023 21:57:55 GMT+0000
APPROVALS:
Protocol


Parexel International 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
Protocol Number:  ISIS 678354-CS3 (AKCEA‑APOCIII‑LRx) 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of 
AKCEA‑APOCIII‑LRX Administered Subcutaneously to Patients 
with Familial Chylomicronemia Syndrome (FCS) 
Statistical Analysis Plan 
Version: 4.0  
Parexel Project Number:  243920 
 
 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 2 of 72 
SPONSOR SIGNATURE PAGE 
 
Approved by: 
 
 
 
 
See electronic signature and date attached at end of document 
 
 
Biometrics  
Ionis Pharmaceuticals, Inc. 
 
 
 
See electronic signature and date attached at end of document 
 
  
 Biometrics 
Ionis Pharmaceuticals, Inc. 
 
 
 
 
See electronic signature and date attached at end of document 
 
  
 Clinical Development 
Ionis Pharmaceuticals, Inc. 
 
 
 
See electronic signature and date attached at end of document 
 
 
PK and Clinical Pharmacology 
Ionis Pharmaceuticals, Inc. 
 
 
 
678354-CS03   Statistical Analysis Plan     | 1.0




Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 4 of 72 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE.................................................................................................... 2 
PAREXEL SIGNATURE PAGE.................................................................................................... 3 
REVISION HISTORY .................................................................................................................... 6 
1. 
INTRODUCTION ..................................................................................................... 17 
2. 
STUDY OBJECTIVES .............................................................................................. 17 
2.1. 
Primary Objective ...................................................................................................... 17 
2.2. 
Secondary Objectives ................................................................................................ 17 
2.3. 
Additional/Exploratory Objective(s) ......................................................................... 18 
3. 
INVESTIGATIONAL PLAN .................................................................................... 18 
3.1. 
Overall Study Design and Plan .................................................................................. 18 
3.2. 
Endpoints ................................................................................................................... 19 
3.2.1. 
Primary Endpoints ..................................................................................................... 19 
3.2.2. 
Secondary Endpoints ................................................................................................. 19 
3.2.3. 
Additional/Exploratory Endpoints ............................................................................. 20 
3.2.4. 
Safety Variables ......................................................................................................... 20 
4. 
STATISTICAL METHODS ...................................................................................... 20 
4.1. 
Data Management and Quality Assurance ................................................................. 20 
4.1.1. 
Central Laboratory Data ............................................................................................ 20 
4.1.2. 
Pharmacokinetic Data ................................................................................................ 20 
4.1.3. 
Adjudicated Data ....................................................................................................... 21 
4.1.4. 
Patient Reported Outcome Assessments.................................................................... 21 
4.1.5. 
Other Data .................................................................................................................. 21 
4.2. 
General Considerations .............................................................................................. 21 
4.2.1. 
Data Presentation ....................................................................................................... 21 
4.2.2. 
Baseline Consideration .............................................................................................. 22 
4.2.3. 
Primary Analysis Time Point, Months 3 and 12, and Treatment Period ................... 23 
4.2.4. 
Visit Windows ........................................................................................................... 23 
4.3. 
Software ..................................................................................................................... 25 
4.4. 
Study Subjects ............................................................................................................ 25 
4.4.1. 
Disposition of Subjects .............................................................................................. 25 
4.4.2. 
Protocol Deviations .................................................................................................... 25 
4.5. 
Analysis Sets .............................................................................................................. 26 
4.6. 
Demographic and Other Baseline Characteristics ..................................................... 26 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 5 of 72 
4.7. 
Medical History ......................................................................................................... 27 
4.8. 
Prior and Concomitant Medication ............................................................................ 27 
4.9. 
Efficacy Evaluation .................................................................................................... 28 
4.9.1. 
Analysis and Data Conventions ................................................................................. 28 
4.9.2. 
Primary Efficacy Variable ......................................................................................... 33 
4.9.3. 
Secondary Efficacy Variables .................................................................................... 37 
4.10. 
Safety Evaluation ....................................................................................................... 41 
4.10.1. 
Extent of Exposure ..................................................................................................... 41 
4.10.2. 
Adverse Events .......................................................................................................... 42 
4.10.3. 
Adverse Events of Special Interest ............................................................................ 44 
4.10.4. 
Other Events of Interest ............................................................................................. 44 
4.10.5. 
Clinical Laboratory Evaluation .................................................................................. 48 
4.10.6. 
Vital Signs and Physical Findings ............................................................................. 53 
4.10.7. 
12-Lead Electrocardiograms (ECG) .......................................................................... 53 
4.10.8. 
Data and Safety Monitoring Board (DSMB) ............................................................. 54 
4.11. 
Other Analyses ........................................................................................................... 54 
4.11.1. 
Pharmacokinetics ....................................................................................................... 54 
4.11.2. 
Immunogenicity Analysis .......................................................................................... 55 
4.11.3. 
Additional/Exploratory Analysis ............................................................................... 58 
4.12. 
Determination of Sample Size ................................................................................... 71 
4.13. 
Changes in the Conduct of the Study or Planned Analysis ....................................... 71 
5. 
REFERENCES .......................................................................................................... 72 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 6 of 72 
REVISION HISTORY 
The following table lists the major modifications to ISIS 678354-CS3 Statistical Analysis Plan 
(SAP) Version 3.0, dated 6 Jun 2023.  Minor changes have also been made throughout the document 
to improve the overall clarity of the original SAP and consistency across the sections 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
2.2 
Secondary Objectives 
List of secondary objectives updated – new added, order changed: 
o 
Percent change in fasting apoC-III from Baseline 
o 
Proportion of patients who achieve ≥ 40% reduction in fasting TG 
from Baseline 
o 
Proportion of patients who achieve fasting TG ≤ 750 mg/dL (8.4 
mmol/L) 
o 
Percent change in fasting apoB-48 from Baseline 
o 
Percent change in fasting non-HDL-C from Baseline 
o 
Adjudicated acute pancreatitis event rate in patients with a 
prior history of pancreatitis within 10 years prior to Screening 
o 
Adjudicated acute pancreatitis event rate in patients with ≥ 2 events 
of adjudicated acute pancreatitis in 5 years prior to enrollment 
o 
Adjudicated acute pancreatitis event rate 
o 
Proportion of patients who achieve ≥ 70% reduction in fasting TG 
from Baseline 
o 
Proportion of patients who achieve fasting TG ≤880 mg/dL 
(10 mmol/L) 
o 
Adjudicated acute pancreatitis event rate in patients with 
≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment 
o 
Proportion of patients who achieve fasting TG ≤ 500 mg/dL 
(5.7 mmol/L) 
 
 
 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 7 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
3.2.2 
Secondary Endpoint 
List of secondary endpoints updated – new added, order changed: 
o 
Percent change in fasting TG from Baseline at 12 months (average 
of Weeks 51 and 53) compared to placebo 
o 
Percent change in fasting apoC-III from Baseline at the primary 
analysis time point compared to placebo 
o 
Percent change in fasting apoC-III from Baseline at 12 months 
compared to placebo 
o 
Proportion of patients who achieve ≥ 40% reduction in fasting TG 
from Baseline at the primary analysis time point compared to 
placebo 
o 
Proportion of patients who achieve fasting TG ≤ 750 mg/dL at the 
primary analysis time point compared to placebo 
o 
Percent change in fasting apoB-48 from Baseline at the primary 
analysis time point compared to placebo 
o 
Percent change in fasting non-HDL-C from Baseline at the primary 
analysis time point compared to placebo 
o 
Adjudicated acute pancreatitis event rate during the Treatment 
Period (Week 1 through Week 53) compared to placebo, in 
patients with a prior history of pancreatitis within 10 years prior 
to Screening 
o 
Adjudicated acute pancreatitis event rate during the Treatment 
Period (Week 1 through Week 53) compared to placebo, in patients 
with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment 
o 
Adjudicated acute pancreatitis event rate during the Treatment 
Period (Week 1 through Week 53) compared to placebo 
o 
Adjudicated acute pancreatitis event rate from Week 13 to 
Week 53 compared to placebo in patients with a prior history of 
pancreatitis within 10 years prior to Screening 
o 
Adjudicated acute pancreatitis event rate from Week 13 to Week 53 
compared to placebo in patients with ≥ 2 events of adjudicated acute 
pancreatitis in 5 years prior to enrollment 
o 
Adjudicated acute pancreatitis event rate from Week 13 to Week 53 
compared to placebo  
o 
Proportion of patients who achieve ≥ 70% reduction in fasting TG 
from Baseline at the primary analysis time point compared to 
placebo 
o 
Percent change in fasting non-HDL-C from Baseline at 12 months 
compared to placebo 
o 
Percent change in fasting apoB-48 from Baseline at 12 months 
compared to placebo 
o 
Proportion of patients who achieve fasting TG ≤ 880 mg/dL at 
the primary analysis time point compared to placebo 
o 
Adjudicated acute pancreatitis event rate during the Treatment 
Period (Week 1 through Week 53) compared to placebo, in 
patients with ≥ 2 events of adjudicated acute pancreatitis in 
5 years prior to enrollment 
o Adjudicated acute pancreatitis event rate from Week 13 to 
Week 53 compared to placebo in patients with ≥ 2 events of 
adjudicated acute pancreatitis in 5 years prior to enrollment 
o 
Proportion of patients who achieve fasting TG ≤ 500 mg/dL at the 
primary analysis time point compared to placebo 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 8 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
4.5 
Analysis Sets 
Definition of PPS updated: 
Per Protocol Set (PPS):  Subset of the FAS who received at least 5 monthly 
doses of Study Drug within the first 6 months (172 days) of the Treatment 
Period, have a baseline TG assessment and who have no significant protocol 
violations that could compromise the interpretation of efficacy 
4.9.1.2 
Handling of Dropouts or 
Missing Data 
Section updated: 
If there is no sufficient number of retrieved dropouts, missing TG value at 
the primary analysis time point will be imputed using a “wash-out” multiple 
imputation approach (Jump to Reference, J2R). With the approach, patients 
treated with ISIS 678354 who discontinue study will have missing post 
discontinuation TG values after the last dosing date multiply imputed 
based on baseline fasting TG, the 2 stratification factors of their own 
treatment group, and the imputation model for the placebo group. Patients in 
the placebo group who discontinue the study will have missing post 
discontinuation TG values multiply imputed based on baseline fasting TG, 
fasting TG values at post-baseline visits and the 2 stratification factors from 
the placebo group.  
The “wash-out” multiple imputation will be preformed in the following 
steps: 
1. The Markov Chain Monte Carlo (MCMC) method will be used 
under the multivariate normality assumption to impute the all 
missing values by treatment group. The variable list for 
imputations will include the baseline value, as well as all available 
post-baseline value, and stratification factors. To conform to the 
multivariate normality assumption, baseline, and post-baseline 
fasting lipid data will be natural log-transformed before the 
imputation process, and the variable values will be back 
transformed to create the imputed data set. The SAS procedure 
PROC MI will be used in the multiple imputation. The MCMC 
method will impute primary analysis time point data one dataset 
forrom each of the 100imputed datasets from the first imputation 
stage. 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. A total of 100 imputed datasets will be created from 
the above 2-stage multiple imputation process…… 
2. A general linear model will be fitted using the data in the 
placebo group for each imputed dataset 
3. For patients in both ISIS 678354 dose groups, the imputed 
values after last dose date will be  replaced with the values 
imputed using J2R method (calculated using the patients’ own 
baseline fasting TG, the 2 stratification factors, and the model 
from step 2) 
4. The variable values will be back transformed from nature log 
scale to the original scale in the final imputed datasets. 
 
 
 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 9 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
4.9.1.3 
Multiplicity 
New secondary endpoints added and testing sequence is updated: 
o 
Secondary endpoint 1: comparison of percent change in fasting TG 
from Baseline to Month 12 between ISIS 678354 80-mg treatment 
group and pooled placebo in FAS 
o 
Secondary endpoint 2: comparison of percent change in fasting 
apoC-III from Baseline to the primary analysis time point between 
ISIS 678354 80-mg treatment group and pooled placebo in FAS 
o 
Secondary endpoint 3: comparison of percent change in fasting 
apoC-III from Baseline to Month 12 between ISIS 678354 80-mg 
treatment group and pooled placebo in FAS 
o 
Secondary endpoint 4: comparison of proportion of patients who 
achieve ≥ 40% reduction in fasting TG from Baseline to the primary 
analysis time point between ISIS 678354 80 mg treatment group and 
pooled placebo in FAS 
o 
Secondary endpoint 5: comparison of proportion of patients who 
achieve fasting TG ≤ 750 mg/dL at the primary analysis time point 
between ISIS 678354 80 mg treatment group and pooled placebo in 
FAS 
o 
Secondary endpoint 5: comparison of percent change in fasting 
apoB-48 from Baseline to the primary analysis time point between 
ISIS 678354 80-mg treatment group and pooled placebo in FAS 
o 
Secondary endpoint 6: comparison of percent change in fasting 
non-HDL-C from Baseline to the primary analysis time point between 
ISIS 678354 80-mg treatment group and pooled placebo in FAS 
o 
Secondary endpoint 7: comparison of percent change in fasting TG 
from Baseline to Month 12 between ISIS 678354 50-mg treatment 
group and pooled placebo in FAS 
o 
Secondary endpoint 8: comparison of percent change in fasting 
apoC-III from Baseline to the primary analysis time point between 
ISIS 678354 50-mg treatment group and pooled placebo in FAS 
o 
Secondary endpoint 9: comparison of percent change in fasting 
apoC-III from Baseline to Month 12 between ISIS 678354 50-mg 
treatment group and pooled placebo in FAS 
o 
Secondary endpoint 10: comparison of proportion of patients who 
achieve ≥ 40% reduction in fasting TG from Baseline to the primary 
analysis time point between ISIS 678354 50-mg treatment group and 
pooled placebo in FAS 
o 
Secondary endpoint 12: comparison of proportion of patients who 
achieve fasting TG ≤ 750 mg/dL at the primary analysis time point 
between ISIS 678354 50 mg treatment group and pooled placebo in 
FAS 
o 
Secondary endpoint 11: comparison of percent change in fasting 
apoB-48 from Baseline to the primary analysis time point between 
ISIS 678354 50-mg treatment group and pooled placebo in FAS 
o 
Secondary endpoint 12: comparison of percent change in fasting 
non-HDL-C from Baseline to the primary analysis time point between 
ISIS 678354 50-mg treatment group and pooled placebo in FAS  
o 
Secondary endpoint 13: comparison of adjudicated acute 
pancreatitis event rate from Week 1 to Week 53 between pooled 
ISIS 678354 treatment group and pooled placebo in the subset of 
FAS with a prior history of pancreatitis within 10 years prior to 
Screening 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 10 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
4.9.1.3 
Multiplicity(Continued) 
o 
Secondary endpoint 14: comparison of adjudicated acute pancreatitis 
event rate from Week 1 to Week 53 between pooled ISIS 678354 
treatment group and pooled placebo in FAS  
o 
Secondary endpoint 15: comparison of adjudicated acute 
pancreatitis event rate from Week 13 to Week 53 between 
pooled ISIS 678354 treatment group and pooled placebo in the 
subset of FAS with a prior history of pancreatitis within 
10 years prior to Screening 
o 
Secondary endpoint 16: comparison of adjudicated acute pancreatitis 
event rate from Week 13 to Week 53 between pooled ISIS 678354 
treatment group and pooled placebo in the FAS 
o 
Secondary endpoint 17: comparison of proportion of patients who 
achieve ≥ 70% reduction in fasting TG from Baseline to the primary 
analysis time point between ISIS 678354 80-mg treatment group and 
pooled placebo in FAS 
o 
Secondary endpoint 18: comparison of percent change in fasting 
non-HDL-C from Baseline to Month 12 between ISIS 678354 
80-mg treatment group and pooled placebo in FAS 
o 
Secondary endpoint 19: comparison of percent change in fasting 
apoB-48 from Baseline to Month 12 between ISIS 678354 80-mg 
treatment group and pooled placebo in FAS 
o 
Secondary endpoint 20: comparison of proportion of patients 
who achieve fasting TG ≤ 880 mg/dL at the primary analysis 
time point between ISIS 678354 80-mg treatment group and 
pooled placebo in the FAS 
o 
Secondary endpoint 21: comparison of proportion of patients who 
achieve ≥ 70% reduction in fasting TG from Baseline to the primary 
analysis time point between ISIS 678354 50-mg treatment group and 
pooled placebo in FAS 
o 
Secondary endpoint 22: comparison of percent change in fasting 
non-HDL-C from Baseline to Month 12 between ISIS 678354 
50-mg treatment group and pooled placebo in FAS 
o 
Secondary endpoint 23: comparison of percent change in fasting 
apoB-48 from Baseline to Month 12 between ISIS 678354 50-mg 
treatment group and pooled placebo in FAS 
o 
Secondary endpoint 24:  comparison of proportion of patients 
who achieve fasting TG ≤ 880 mg/dL at the primary analysis 
time point between ISIS 678354 50-mg treatment group and 
pooled placebo in the FAS 
o 
Secondary endpoint 25: comparison of adjudicated acute pancreatitis 
event rate from Week 1 to Week 53 between pooled ISIS 678354 
treatment group and pooled placebo in the subset of FAS with 
≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment 
o 
Secondary endpoint 26:  comparison of adjudicated acute 
pancreatitis event rate from Week 13 to Week 53 between pooled 
ISIS 678354 treatment group and pooled placebo in the subset of 
FAS with ≥ 2 events of adjudicated acute pancreatitis in 5 years 
prior to enrollment 
 
 
 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 11 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
4.9.1.3 
Multiplicity(Continued) 
o 
Secondary endpoint 27: comparison of proportion of patients who 
achieve fasting TG ≤ 500 mg/dL at the primary analysis time point 
between ISIS 678354 80-mg treatment group and pooled placebo in 
FAS 
o 
Secondary endpoint 28: comparison of proportion of patients who 
achieve fasting TG ≤ 500 mg/dL at the primary analysis time point 
between ISIS 678354 50-mg treatment group and pooled placebo in 
FAS 
4.9.2. 
 Primary Efficacy Variable 
Section updated: 
1) Patients with missing TG value at the primary analysis time point 
will be imputed using a pattern mixture model. Specifically, for 
patients treated with ISIS 678354 who discontinue the study 
treatment due to AE or lack of efficacy (i.e., informative missing), 
their missing fasting TG data after treatment discontinuation the last 
dosing date 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 withdrawal 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 treatment group.  
2) All patients treated with ISIS 678354 who discontinue the study will 
have missing post treatment discontinuation TG values after the 
last dosing date multiply using the CIR approach based on the 
estimates from the placebo patients. Missing TG values for placebo 
patients will be imputed based on the distribution of the placebo 
group. 
4.9.3.2. 
Proportion of Patients who 
Achieve ≥ 40% Reduction 
in Fasting TG from 
Baseline at the Primary 
Analysis Time Point   
Section updated: 
Sensitivity Analysis 1: An additional analysis will be conducted in the FAS, 
in which all patients who have missing data and discontinue study 
treatment before Week 23 will be considered as non-responders. 
4.9.3.4 
Proportion of Patients who 
Achieve Fasting TG 
≤ 880 mg/dL at Primary 
Analysis Time Point 
• 
TG reduction level changed to 880: 
o 
The proportion of patients who achieve fasting TG ≤ 750 
880 mg/dL 
 
 
 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 12 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
4.9.3.5 
Adjudicated Acute 
Pancreatitis Event Rate 
from Week 1 to Week 53 in 
the Subset of FAS with a 
prior history of pancreatitis 
within 10 years prior to 
Screening 
Section changed to: 
o 
Adjudicated Acute Pancreatitis Event Rate from Week 1 to 
Week 53 in the Subset of FAS with a prior history of pancreatitis 
within 10 years prior to Screening ≥ 2 Events of Adjudicated 
Acute Pancreatitis in 5 years Prior to Enrollment 
Description added: 
o 
The adjudicated acute pancreatitis event rate from Week 1 to 
Week 53 in the subset of FAS with a prior history of pancreatitis 
within 10 years prior to Screening≥ 2 events of adjudicated acute 
pancreatitis in 5 years prior to enrollment will be compared 
between pooled ISIS 678354 treatment and placebo group using a 
Negative Binomial regression model with the treatment group and 
previous treatment with volanesorsen (yes/no) as the factors, and 
number of adjudicated acute pancreatitis events in 5 years prior to 
the enrollment, i.e., events occurred within 1826 days (calculated 
by 365.25 times 5 and rounded to integer) before the first dose 
date and up to the first dose date and time,  as a covariate. 
4.9.3.7 
Adjudicated Acute 
Pancreatitis Event Rate 
from Week 13 to Week 53 
in the Subset of FAS with a 
prior history of pancreatitis 
within 10 years prior to 
Screening 
• 
Section changed to: 
o 
Adjudicated Acute Pancreatitis Event Rate from Week 13 to 
Week 53 in the Subset of FAS with a prior history of pancreatitis 
within 10 years prior to Screening ≥ 2 Events of Adjudicated 
Acute Pancreatitis in 5 years Prior to Enrollment 
4.9.3.9.  Adjudicated Acute 
Pancreatitis Event Rate 
from Week 1 to Week 53 in 
the Subset of FAS with 
≥ 2 Events of Adjudicated 
Acute Pancreatitis in 
5 years Prior to Enrollment 
• 
Section added 
4.9.3.10 
Adjudicated Acute 
Pancreatitis Event Rate 
from Week 13 to Week 53 
in the Subset of FAS with 
≥ 2 Events of Adjudicated 
Acute Pancreatitis in 
5 years Prior to Enrollment 
• 
Section added 
4.9.3.12. Proportion of atients who 
Achieve Fasting TG ≤ 500 
mg/dL at Primary Analysis 
Time Point 
Baseline fasting TG level changed to 500 mg/dL: 
with baseline fating TG > 750 500 mg/dL. 
4.10. 
Safety Evaluation 
Analyses added: 
Risk difference and corresponding 95% CI in the crude incidence rates 
between each active treatment group (or total ISIS 678354) and pooled 
placebo group in selected safety endpoint will be provided. The crude 
incidence rate (or 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 Miettinen-Nurminen (MN) method.  
 
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 13 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
4.10.1 
Extent of Exposure 
Added analysis: 
o 
A summary of number of days of dose interruption. 
4.10.3. 
Adverse Events of Special 
Interest 
Added analyses: 
The number and percentage of patients experiencing events as well as 
the total number of reported events, classified by SOC and PT, will be 
tabulated by treatment group. 
The following additional analyses may be provided if supported by 
data: 
o 
A cumulative incidence plot  
o 
Risk difference and its 95% CI in the crude incidence rates 
between each active treatment group (or total ISIS 678354) and 
pooled placebo group. The analysis methods are detailed in 
Section 4.10 of this SAP. 
o 
Exposure adjusted incidence rates (EAIRs) and risk difference 
(or ratio) in EAIRs may also be provided, if deemed necessary. 
EAIR is defined as the number of patients who experienced at 
least one event times 100 divided by total patient-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 (i.e., last participation date 
minus first dose date plus one day divided by 365.25). 
o Exposure adjusted event rates (EAERs), defined as the number 
of events times 100 divided by the total duration in the on-study 
period in year. 
4.10.4.1. Local Cutaneous Reactions 
at the Injection Site 
Added analysis: 
In addition, for patients who experienced LCRIS, time to onset of the first 
event, the number of injections prior to the first LCRIS will also be 
summarized descriptively by treatment group and total ISIS 678354 treated. 
4.10.4.2 
Injection Site Reaction 
Added analysis: 
In addition, for patients who experienced ISR, time to onset of the first 
event, the number of injections prior to the first ISR will also be 
summarized descriptively by treatment group and total ISIS 678354 treated. 
4.10.4.3 
Flu-like Reactions 
Section updated: 
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 are defined as adverse events with PTs 
including either (A) Influenza like illness or (B) Pyrexia or Feeling hot or 
Body temperature increased, plus at least two of the following symptoms 
with the PTs: Chills, Myalgia, or Arthralgia, starting on day of injection or 
the next day. 
….. 
For the subset of patients experiencing FLR(s), the time to onset of first 
FLR will be summarized using descriptive statistics. 
 
 
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Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 14 of 72 
Section 
Section Title 
Description of Changes (Additions in bold. Deletions in strikethrough) 
4.10.4.4. Bleeding TEAE 
Section updated: 
Bleeding TEAEs will be analyzed for the following categories. The 
number and percentage of patients experiencing events as well as the 
number of reported events, classified by SOC and PT, will be tabulated 
by treatment group. The risk different (95% CI) in the crude incidence 
rates between each active treatment group (or total ISIS 678354) and 
pooled placebo group will be provided. 
o 
Bleeding TEAEs (defined based on the ‘Haemorrhages’ 
Standardized MedDRA Query [SMQ, both narrow and broad 
scope]) 
o 
Clinical bleeding TEAEs, i.e. bleeding TEAEs excluding events 
at the injection site and events related to a laboratory value 
o 
Clinical bleeding events with concomitant anticoagulant or 
antiplatelet medication 
o 
Clinical bleeding events without concomitant anticoagulant or 
antiplatelet medication 
Bleeding AEs will be identified based on the Haemorrhages (SMQ) Export 
from MedDRA and summarized by MedDRA system organ class and 
preferred term and by treatment group. 
Bleeding AEs excluding bleeding at the injection will be summarized by 
MedDRA system organ class and preferred term and by treatment group. 
4.10.4.5. Thrombocytopenia TEAE 
• 
Section added 
4.10.4.6 
Hypersensitivity TEAE 
• 
Section added 
4.10.4.7 
Renal Impairment TEAE 
• 
Section added 
4.10.4.8. Abnormal Liver Function 
TEAE 
• 
Section added 
4.10.5. 
Clinical Laboratory 
Evaluation 
Categories for abnormality levels updated.  
 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation / Acronym 
Definition / Expansion 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
apo 
apolipoprotein  
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CIR 
increment from reference 
CRF 
case report form 
CRO 
contract research organization 
CTR 
clinical trial report 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DNA 
deoxyribonucleic acid 
DRM 
data review meeting 
DSMB 
data and safety monitoring board 
EAIR 
exposure adjusted incidence rate 
ECG 
electrocardiogram 
EAER 
exposure adjusted event rate 
eDISH 
evaluation of Drug Induced Serious Hepatoxicity 
eGFR 
estimated glomerular filtration rate 
EOS 
end-of-study 
ER 
emergency room 
ET 
early termination 
FLRs 
flu-like reactions  
FCS 
familial chylomicronemia syndrome 
FMQ 
FDA medical query 
GFR 
glomerular filtration rate 
HbA1c 
glycated hemoglobin 
HDL-C 
high-density lipoprotein cholesterol 
HRQoL 
health-related quality of life 
IB 
investigator’s brochure 
ICF 
informed consent form 
IEC 
independent ethics committee 
IM 
immunogenicity 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent-to-treat 
LDL 
low-density lipoprotein 
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TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 16 of 72 
Abbreviation / Acronym 
Definition / Expansion 
MACE 
major adverse cardiovascular events 
MAR 
missing at random 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
medical dictionary for regulatory activities 
MN 
Miettinen-Nurminen 
MNAR 
missing not at random 
NA 
not available 
OLE 
open-label extension 
PD 
protocol deviation 
PK 
pharmacokinetic 
PMM 
pattern mixture model 
PPS 
per-protocol set 
PT 
preferred term 
ROW 
rest of world 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TG 
triglycerides 
UACR 
urinary albumin/creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urinary protein/creatinine ratio 
VLDL 
very low-density lipoprotein 
WBCs 
white blood cells 
WHO-DD 
world health organization - drug dictionary 
 
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ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 17 of 72 
1. 
INTRODUCTION 
The analyses described in this SAP are based upon the following Ionis study documents: 
• Study Protocol, Amendment 7 – ROW (October 26, 2022)  
• Study Protocol, Amendment 8 – UK (February 23, 2023) 
• Study Protocol, Amendment 6 – Germany (December 7, 2021) 
• Study Protocol, Amendment 9 – France (October 17, 2022) 
• Study Protocol, Amendment 9 –ROW (August 2, 2023) 
This SAP details the procedures for the pharmacokinetic (PK), efficacy and safety statistical methods 
used to analyze the data. 
Any deviations from the final version of this Statistical Analysis Plan (SAP) will be substantiated by 
sound statistical rationale and will be documented in the final clinical study report.  
Revision of this SAP will not be required for any subsequent amendments to the protocol which do 
not change the analyses described in this SAP. Revisions to specifics such as blood sample collection 
times, etc. will not require an update to the SAP. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To evaluate the efficacy of ISIS 678354 (olezarsen) as compared to placebo on the percent change 
in fasting triglycerides (TG) from Baseline 
2.2. 
Secondary Objectives 
To evaluate the efficacy of ISIS 678354 as compared to placebo on the following: 
• Percent change in fasting apoC-III from Baseline 
• Proportion of patients who achieve ≥ 40% reduction in fasting TG from Baseline 
• Percent change in fasting apoB-48 from Baseline 
• Percent change in fasting non-HDL-C from Baseline 
• Adjudicated acute pancreatitis event rate in patients with a prior history of pancreatitis 
within 10 years prior to Screening 
• Adjudicated acute pancreatitis event rate 
• Proportion of patients who achieve ≥ 70% reduction in fasting TG from Baseline 
• Proportion of patients who achieve fasting TG ≤ 880 mg/dL (10 mmol/L) 
• Adjudicated acute pancreatitis event rate in patients with ≥ 2 events of adjudicated acute 
pancreatitis in 5 years prior to enrollment 
• Proportion of patients who achieve fasting TG ≤ 500 mg/dL (5.7 mmol/L) 
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2.3. 
Additional/Exploratory Objective(s) 
To evaluate the effect of ISIS 678354 as compared to placebo on: 
• Patient-reported abdominal pain, other FCS-related symptoms (physical fatigue, difficulty 
thinking and diarrhea), diet, and impacts, and health-related quality of life (HRQoL), pain 
interference and cognitive function.  
• Emergency room (ER) visits, incidence of all-cause hospitalizations and total inpatient days 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a multi-center, randomized, double-blind, placebo-controlled study. Eligible patients will 
enter an approximately 4-week, but no more than 8-week, Screening Period that includes an at least 
2-week Diet Stabilization/Run-In Period for patients not already on a stable diet, and an 
approximately 2-week Qualification Period. Following qualification, approximately 60 eligible 
patients will be randomized 1:1 to Cohort A (50 mg) or Cohort B (80 mg) and each cohort further 
randomized 2:1 to receive ISIS 678354 or placebo in a 53-week Treatment Period. Patients in Cohort 
A will receive 50 mg of ISIS 678354 once every 4 weeks or matching volume of placebo (0.5 mL) 
Weeks 1-49, of the Treatment Period. Patients in Cohort B will receive 80 mg ISIS 678354 once 
every 4 weeks or matching volume of placebo (0.8 mL) Weeks 1-49 of the Treatment Period. 
Randomization will be stratified by (1) prior history of pancreatitis (within 10 years prior to 
Screening) and (2) previous treatment with volanesorsen. Dietary counseling will commence at the 
start of the Diet Stabilization Period and will be reinforced at intervals throughout the Treatment and 
Follow-up Period. Following the Week 53 visit, eligible patients may elect to enroll in an open-label 
extension (OLE) study pending study approval by the institutional review board/independent ethics 
committee (IRB/IEC) and the appropriate regulatory authority. Patients not participating in the OLE 
will enter the 13-week Post Treatment Evaluation Period. The primary endpoint for the study will be 
evaluated after the last patient has completed the Week 53/ET visit and will be based on the percent 
change in fasting TG from Baseline at the primary analysis time point (Month 6). 
The study for an individual patient will generally consist of the following periods: 
• A screening period of up to 8 weeks is given to complete the screening and baseline 
assessments. An approximately 4-week but no more than 8-week Screening Period including 
a Diet Stabilization Period of at least 2 weeks and an approximately 2-week Qualification 
Period (patients on stable diet, for optimal control of TGs and disease management, known to 
the Investigator and followed at the site may go from Screening to Qualification without the 
Diet Run-In Period) 
• The Treatment Period is 53 weeks. Eligible patients will have assessments at specified 
intervals throughout the 53-week Treatment Period. During the Treatment Period, Study Drug 
is administered by SC injection once every 4 weeks (Week 1 through Week 49). 
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• The Post-Treatment Follow-up Period is 13 weeks with assessments. Alternatively, following 
the Week 53 visit, eligible patients may elect to enroll in an OLE study pending study approval 
of this proposed study by the IRB/IEC and the appropriate regulatory authority. 
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.  
3.2. 
Endpoints 
The primary analysis time point is at the end of Month 6 where the value is defined as the average of 
Weeks 23, 25 and 27 assessments. 
3.2.1. 
Primary Endpoints 
The primary endpoint is the percent change in fasting TG from Baseline at the primary analysis time 
point compared to placebo. 
3.2.2. 
Secondary Endpoints 
The secondary endpoints include the following: 
• Percent change in fasting TG from Baseline at 12 months (average of Weeks 51 and 53) 
compared to placebo 
• Percent change in fasting apoC-III from Baseline at the primary analysis time point 
compared to placebo 
• Percent change in fasting apoC-III from Baseline at 12 months compared to placebo 
• Proportion of patients who achieve ≥ 40% reduction in fasting TG from Baseline at the 
primary analysis time point compared to placebo 
• Percent change in fasting apoB-48 from Baseline at the primary analysis time point 
compared to placebo 
• Percent change in fasting non-HDL-C from Baseline at the primary analysis time point 
compared to placebo 
• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1 through 
Week 53) compared to placebo, in patients with a prior history of pancreatitis within 
10 years prior to Screening 
• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1 through 
Week 53) compared to placebo 
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to placebo in 
patients with a prior history of pancreatitis within 10 years prior to Screening 
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to placebo  
• Proportion of patients who achieve ≥ 70% reduction in fasting TG from Baseline at the 
primary analysis time point compared to placebo 
• Percent change in fasting non-HDL-C from Baseline at 12 months compared to placebo 
• Percent change in fasting apoB-48 from Baseline at 12 months compared to placebo 
• Proportion of patients who achieve fasting TG ≤ 880 mg/dL at the primary analysis time 
point compared to placebo 
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Project Document Effective Date: 15 Aug 2023 
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• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1 through 
Week 53) compared to placebo, in patients with ≥ 2 events of adjudicated acute pancreatitis 
in 5 years prior to enrollment 
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to placebo in 
patients with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment 
• Proportion of patients who achieve fasting TG ≤ 500 mg/dL at the primary analysis time 
point compared to placebo 
3.2.3. 
Additional/Exploratory Endpoints 
To evaluate the effect of ISIS 678354 as compared to placebo on: 
• Patient-reported abdominal pain, other FCS-related symptoms (physical fatigue, difficulty 
thinking and diarrhea), diet, and impacts, HRQoL, pain interference and cognitive function.  
• ER visits, incidence of all-cause hospitalizations and total inpatient days 
3.2.4. 
Safety Variables 
Safety and tolerability assessments include adverse events, clinical laboratory tests, 
electrocardiogram (ECGs), use of concomitant medications, and independently adjudicated event 
rates of Major Adverse Cardiovascular Events (MACE) for ISIS 678354 as compared to placebo. 
4. 
STATISTICAL METHODS 
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 data 
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 Sponsor, Investigator and patients will be kept blinded to post-baseline laboratory lipid panel 
results (TG, apoC-III, total cholesterol, LDL cholesterol, HDL cholesterol, apoB, apoB-48, 
chylomicron-TG, VLDL, non-HDL-C, and apoA-1) which can jeopardize the blinding of treatment 
allocation, alter Investigator’s clinical practice, or are part of study endpoints to avoid bias in the 
conduct of the study. Beginning at Week 27, if a patient has an LDL-C > 130 mg/dL (> 100 mg/dL 
for patients with T2DM or CAD with Baseline LDL-C > 100 mg/dL) on 2 consecutive visits, the 
LDL-C values for this patient will be unblinded for the remainder of the study. 
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 
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Page 21 of 72 
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. 
4.1.3. 
Adjudicated Data 
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) 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. 
All AEs and SAEs that occur during the study that are consistent with a MACE will be adjudicated 
by a blinded, independent committee as outlined in the MACE Adjudication Charter. 
4.1.4. 
Patient Reported Outcome Assessments 
The patient reported outcome assessments will be captured by YPrime eCOA System. Patients will 
enter their assessments into the system using a study-dedicated tablet and handheld devices. Ionis and 
YPrime are responsible for the format of the electronic data transfers and the transfer schedule. The 
patient reported outcome assessments will not be stored in the EDC system. Ionis and YPrime are 
also responsible for the review of the data. This process involves reviewing the patient and visit 
identifiers in the assessment data against the data identifiers collected in the EDC system.  The 
YPrime system for data collection includes built-in measures to prevent missing items for any 
completed questionnaire. 
4.1.5. 
Other Data 
Genetic lab data will be provided by PreventionGenetics. Platelet antibody data will be provided by 
Versiti Wisconsin, Inc. Platelet and Immunology Reference Lab. Ionis, PreventionGenetics and 
Versiti Wisconsin are responsible for the review of the data, the format of the electronic data transfers 
and the transfer schedule. These data will also not be stored in the EDC system but will be transferred 
to Ionis as external data. 
4.2. 
General Considerations 
4.2.1. 
Data Presentation 
Descriptive summary statistics including n, mean, median, standard error, standard deviation, 
interquartile range (25th percentile, 75th percentile), 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. 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 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 the number of subjects providing data at the relevant 
time point (n), frequency counts and percentages.   
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts.  
Percentages will be calculated using n as the denominator.   
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
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All statistical tests will be conducted using 2-sided tests with 5% Type 1 error rates unless otherwise 
stated. 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 will be presented to one more decimal place than the raw data. 
Any outliers that are detected during the review of the data before database lock will be investigated. 
If necessary, queries will be issued to the Investigator, to either correct or confirm the outlier. 
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. The secondary endpoints will be 
assessed in the FAS. All safety assessments will be performed on the Safety Set (SS). PK endpoints 
will be assessed in the PK Set as applicable.  
Efficacy results will be summarized under the treatment to which patients are randomized. Safety and 
PK results will be summarized under the treatment which patients actually received. Should there be 
any cases in which a patient received treatment other than what was randomized, such cases will be 
discussed in the study report and noted in footnotes where applicable. 
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.   
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel (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 provided in the data lstings if supported 
by data. Additional listings may be provided for all patients impacted by COVID-19 during conduct 
of the study and additional summary (s) and/or analyses may be provided if deemed necessary. 
4.2.2. 
Baseline Consideration 
Baseline for lipid measurements is defined as the average of the pre-dose measurement on Day 1 and 
the last measurement closest to Day 1 (last measurements from Qualification period and Screening 
period), prior to administration of the first dose of Study Drug. If 1 of the 2 measurements is missing, 
then the other measurement will be assigned as the baseline value. If all pre-dose measurements are 
missing, then the baseline will be set as missing. Missing baseline values will be imputed using the 
multiple imputation method described in Section 4.9.1.2 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. 
Baseline consideration for exploratory endpoints: 
1. Average worst FCS Symptoms (abdominal pain, physical fatigue, difficulty thinking, 
diarrhea, and composite symptom score): baseline is defined as the average during the 
screening period and up to Day 1; an alternative baseline is defined as single observation 
collected at the first day of screening with a two-week recall. 
2. Highest worst FCS Symptoms: baseline is defined as the highest (worst) score during the 
screening period and up to Day 1. 
3. FCS Impacts, PROMIS pain interference, HR-QoL (PROMIS 29+2 Profile v2.1), 
PROMIS cognitive function, and Patient Global Impression of Severity (PGIS): baseline 
is defined as the last non-missing assessment on or prior to  Day 1 
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The ECG measurements will be performed in triplicate at each visit. Baseline for continues variables 
is defined as the average of the last non-missing triplicate prior to the first dose of Study Drug.; 
Baseline for categorical variable is defined as the worst of the last non-missing triplicate prior to the 
first dose of Study Drug. If only one or two measurements are available, the baseline will be 
determined from the available measurements. 
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. 
4.2.3. 
Primary Analysis Time Point, Months 3 and 12, and Treatment Period 
The primary analysis time point is defined as the average of Weeks 23, 25, and 27. If 1 or 2 of the 
3 assessments are missing, then non-missing assessments will be used. Month 3 is defined as the 
average of Weeks 13 and 17. Month 12 is defined as the average of Weeks 51 and 53. For Month 3 
or Month 12, if 1 assessment is missing, then non-missing assessment will be used. 
The treatment period is defined as the time period from the first dose administration to the earliest 
date from 42 days after the last dose of Study Drug and last contact date within the study.  
4.2.4. 
Visit Windows 
The efficacy and exploratory measures will be mapped to analysis visits according to the visit 
windows in the table 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, due to the fact that most patients are expected to roll into the 
OLE study, these data will only be provided in patient listings for evaluation of individual patient 
safety rather than being tabulated. Therefore, no visit windows are needed for data analysis for these 
visits. 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.   
For Daily FCS Symptoms questionnaire using average, data in the same visit window will be 
averaged. 
For Daily FCS Symptoms questionnaire using the highest (worst) score, the highest score in each 
visit window will be determined. 
For other data, 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. 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.  
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Project Document Effective Date: 15 Aug 2023 
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Page 24 of 72 
Efficacy/PD measure 
Nominal Visit (Target Day)  
Analysis Visit Window (Day)  
Lipid Panel 
Week 5 (Day 29) 
2-43 
 
Week 9 (Day 57) 
44-71 
 
Week 13 (Day 85) 
72-99 
 
Week 17 (Day 113) 
100-127 
 
Week 21 (Day141) 
128-148 
 
Week 23 (Day 156) 
149-162 
 
Week 25 (Day 169) 
163-176 
 
Week 27 (Day 183) 
177-190 
 
Week 29 (Day 197) 
191-225 
 
Week 37 (Day 253) 
226-281 
 
Week 45 (Day 309) 
282-330 
 
Week 51 (Day 351) 
331-358 
 
Week 53 (Day 365) 
359-379a 
Daily FCS Symptoms  
Week 2 (Day 8) 
2-8 
 
Week 3 (Day 15) – Week 53 (Day 365) 
(Week-1)*7-5 to (Week-1)*7+1 
FCS Impacts; Pain Interference & 
PGIS 
Week 5 (Day 29) 
2-43 
Week 9 (Day 57) 
44-71 
 
Week 13 (Day 85) 
72-99 
 
Week 17 (Day 113) 
100-127 
 
Week 21 (Day141) 
128-148 
  
Week 23 (Day 156) 
149-162 
 
Week 25 (Day 169) 
163-176 
 
Week 27 (Day 183) 
177-190 
 
Week 29 (Day 197) 
191-211 
 
Week 33 (Day 225) 
212-239 
 
Week 37 (Day 253) 
240-267 
 
Week 41 (Day 281) 
268-295 
 
Week 45 (Day 309) 
296-323 
 
Week 49 (Day 337) 
324-344 
 
Week 51 (Day 351) 
345-358 
 
Week 53 (Day 365) 
359-379 a 
PGIC 
Week 23 (Day 156) 
149-162 
 
Week 25 (Day 169) 
163-176 
 
Week 27 (Day 183) 
177-190 
 
Week 51 (Day 351) 
331-358 
 
Week 53 (Day 365) 
359-379 a 
Health-related QOL (PROMIS 29+2 
Profile v2.1) & PROMIS Cognitive 
Function 
Week 13 (Day 85) 
72-99 
Week 23 (Day 156) 
149-162 
Week 25 (Day 169) 
163-176 
Week 27 (Day 183) 
177-190 
 
Week 51 (Day 351) 
331-358 
 
Week 53 (Day 365) 
359-379 a 
a 379 represents the middle point between the target days for the Week 53 visit and the first post-treatment assessment 
visit. 
 
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Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 25 of 72 
All other by-visit assessments will be summarized using the visit labels provided in the data.  Multiple 
results with the same visit label will be averaged. Unscheduled results from the central lab will not 
be included in the by-visit summaries but will be used in the determination of baseline, laboratory 
abnormality summaries and shift analyses, and presented in data listings. Local lab data will be only 
used in platelet analyses (including by visit summary, abnormality summaries, and shift from 
Baseline to worst post-baseline), and presented in data listings. For other safety lab parameters, local 
lab data will not be included in any analyses and data summaries. 
4.3. 
Software 
All report outputs will be produced using SAS® Version 9.4 or a later version in a secure and 
validated environment.   
4.4. 
Study Subjects 
4.4.1. 
Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to study completion. 
The following summaries will be provided: 
• A summary of the number and percentage of subjects who were screened, randomized, and 
subjects who are excluded prior to randomization by major reason and overall, using the all 
screening patients. 
• A summary of the number and percentage of patients treated (with at least one dose or partial 
dose of IMP) and terminating from treatment, and the number and percentage of major reason 
of patient terminating from treatment by treatment group, total ISIS 678354-treated 
(50 mg +80 mg) and overall. 
• A summary of the number and percentage of patients completed the study and terminating 
from the study, and the number and percentage of major reason of patient terminating from 
the study, by treatment group, total ISIS 678354-treated (50 mg + 80 mg) and overall.  
• The percentage of patients treated, the percentage of patients who discontinued from treatment 
and the percentage of patients who discontinued from study will be calculated based on the 
number of patients randomized. 
A by-subject listing of disposition data will be provided based on the randomized subjects. Listing of 
eligibility criteria will be provided. A separate disposition listing for screen failures will also be 
provided. 
4.4.2. 
Protocol Deviations 
Protocol Deviations (PDs) will be classified as “major” or “minor” based on study protocol deviation 
guidance. All protocol deviations and major protocol deviations will be summarized by deviation 
category. The PD summaries will include the number and percentage of subjects with a PD by 
treatment group and overall, and by type of deviation, based on the randomized subjects. 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 
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TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 26 of 72 
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. 
Analysis Sets 
The following analysis populations will be used for the analysis of data as described within each 
analysis set: 
Full Analysis Set (FAS): All patients who are randomized and received any amount of Study Drug 
(ISIS 678354 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. 
Per Protocol Set (PPS): Subset of the FAS who received at least 5 monthly doses of Study Drug 
within the first 6 months (172 days) of the Treatment Period, and who have no significant protocol 
violations that could compromise the interpretation of efficacy. Significant violations 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 at least 1 dose of ISIS 678354, and have 
at least 1 evaluable concentration result post-first dose. This population will be used for analysis of 
PK data. 
Analysis populations will be listed and also summarized with counts and percentages by treatment 
group and overall.  
4.6. 
Demographic and Other Baseline Characteristics 
Demographic data include age, age category (< 18, 18 to 64, ≥ 65 years), gender, ethnicity, race, 
weight, and body mass index (BMI). 
Baseline characteristics include genetic confirmation and baseline lipids profile (fasting TG, apoC-III, 
total cholesterol, LDL cholesterol, HDL cholesterol, apoB, apoB-48, chylomicron-TG, VLDL, 
non-HDL-C, and apoA-1).    
The following summaries will be provided: 
• A summary of the demographic data, and baseline characteristics will be provided using the 
FAS population (Section 4.5). 
• A summary of the demographic data and baseline characteristics will be provided using the 
PPS population (Section 4.5). 
• A summary of the demographic data and baseline characteristics will be provided using the 
Safety Set (Section 4.5). 
A by-subject listing of the demographic data and the baseline characteristics will be provided for all 
randomized subjects. 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 27 of 72 
4.7. 
Medical History 
The general medical history will be summarized using the Safety Set (Section 4.5). Frequency table 
will be provided by treatment group and overall, system organ class (SOC) and preferred term (PT), 
where SOC and PT are coded by Medical Dictionary for Regulatory Activities (MedDRA). The final 
MedDRA version used will be designated in the clinical study report.   
A by-subject listing of medical history, including the reported term, the coded term, the start date, 
and the end date will be provided for all randomized subjects. 
A separate table will be created for the targeted medical history using the Safety Set, and will include 
diabetes mellitus history, cardiac-related history (acute MI, percutaneous coronary intervention (PCI), 
CABG, unstable angina, heart failure, Stroke (CVA)/TIA, and revascularization), and pancreatitis 
history. 
4.8. 
Prior and Concomitant Medication 
Prior medications include medications started prior to the first dose of study medication regardless 
whether continued while on treatment or not. Concomitant medications include medications that 
patients are exposed to on or after the first dose of study medication. Partial or missing medication 
start date or end date will be imputed by the following imputation rules: 
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 
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 medication will be summarized using the Safety Set (Section 4.5) separately. 
Frequency table will be provided by treatment group, anatomical therapeutic chemical (ATC) drug 
class and preferred term (PT), where ATC and PT are coded by World Health Organization-Drug 
Dictionary Enhanced (WHO-DDE). The final WHO-DDE version used will be designated in the 
clinical study report. 
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Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 28 of 72 
The number and percentage of patients in each of the following categories will also be summarized 
by treatment group using the Safety Set: 
• Not taking stains at baseline 
o Initiated statins after study drug administration 
• Taking statins at baseline 
o Increased statin dose or switched to higher intensity after study drug administration. 
A by-subject listing of prior and concomitant medications will be provided using the Safety Set. 
4.9. 
Efficacy Evaluation 
4.9.1. 
Analysis and Data Conventions 
4.9.1.1. 
Hypothesis 
The study hypothesis is that ISIS 678354 can significantly improve efficacy parameters and is 
well-tolerated for patients with FCS. The null hypothesis for the treatment comparison will be that 
there is no difference between ISIS 678354 and Placebo in the percent change in fasting TG from 
Baseline at the primary analysis time point. The alternative hypothesis will be that there is a 
difference.   
Symbolically, this is expressed as follows: 
H(0): (test) = (reference) 
H(1): (test) ≠ (reference)  
4.9.1.2. 
Handling of Dropouts or Missing Data 
If there is missing TG data at baseline and primary analysis time point, a two-stage multiple 
imputation approach will be utilized. 
First, patients with a missing fasting TG at the baseline will have missing values multiply imputed 
based on the observed baseline assessments from other patients. The Markov Chain Monte Carlo 
(MCMC) method will be used to impute the missing values. The imputation model will include 
baseline fasting TG value and 2 stratification factors (history of pancreatitis and previous treatment 
with Volanesorsen) (Schafer 1997; 1999). The TG values will be natural log-transformed before the 
imputation process, then back transformed after imputation to create the imputed data set.  The SAS 
procedure PROC MI will be used to create 100 imputed datasets. 
The following pseudo SAS code and seed (2438291) will be used to perform the multiple imputation 
for missing TG at baseline: 
   proc mi data = TG seed = 2438291 nimpute = 100 out=TG2; 
transform log(baseline);  
      Mcmc;  
  var PANCR Volan baseline; 
   run; 
The imputed baseline values will be merged with the observed post-baseline data and used for the 
second stage of imputation. 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 29 of 72 
In the second stage of imputation, patients with a missing fasting TG at the primary analysis time 
point will have missing values multiply imputed based on the known assessments from the retrieved 
dropouts (patients who discontinue treatment before Week 23 but still have TG assessments at 
Weeks 23, 25, or 27), if there are a sufficient number of retrieved dropouts. The imputation model 
will contain the following variables: baseline fasting TG value, fasting TG values at post-baseline 
visits and 2 stratification factors (history of pancreatitis and previous treatment with volanesorsen), 
and the multiple imputation will be stratified by treatment group.   
If there is no sufficient number of retrieved dropouts, missing TG value at the primary analysis time 
point will be imputed using a “wash-out” multiple imputation approach (Jump to Reference, J2R). 
With the approach, patients treated with ISIS 678354 will have missing TG values after the last dosing 
date multiply imputed based on baseline fasting TG, the 2 stratification factors of their own treatment 
group, and the imputation model for the placebo group. Patients in the placebo group will have 
missing TG values multiply imputed based on baseline fasting TG, fasting TG values at post-baseline 
visits and the 2 stratification factors from the placebo group.  
The “wash-out” multiple imputation will be preformed in the following steps: 
1. The Markov Chain Monte Carlo (MCMC) method will be used under the multivariate 
normality assumption to impute all missing values by treatment group. The variable list for 
imputations will include the baseline value, as well as all available post-baseline value, and 
stratification factors. To conform to the multivariate normality assumption, baseline, and 
post-baseline fasting lipid data will be natural log-transformed before the imputation 
process, and the variable values will be back transformed to create the imputed data set. The 
SAS procedure PROC MI will be used in the multiple imputation. The MCMC method will 
impute primary analysis time point data for each of the 100 datasets from the first 
imputation stage.  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. A total of 100 imputed datasets will be created from 
the above 2-stage multiple imputation process. 
The following pseudo SAS code and seed (2438291) will be used to perform the multiple 
imputation for each treatment group: 
   proc mi data = TG2 seed = 2438291 nimpute = 1; 
transform log(baseline) log(week5) log(week9) log(month3)     
log(week21) log(month6) log(week29) log(week37) log(week45) 
Log(month12);  
      mcmc; 
  var PANCR Volan baseline week5 week9 month3 week21 month6 
week29 week37 week45 month12; 
      by _imputation_; 
   run; 
If there is no missing data at baseline, then the baseline imputation will not be performed. 
The second stage of imputation will be performed to create 100 imputed datasets.  
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Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 30 of 72 
2. A general linear model will be fitted using the data in the placebo group for each imputed 
dataset 
3. For patients in both ISIS 678354 dose groups, the imputed values after last dose date will be  
replaced with the values imputed using J2R method (calculated using the patients’ own 
baseline fasting TG, the 2 stratification factors, and the model from step 2)  
4. The variable values will be back transformed from nature log scale to the original scale in 
the final imputed datasets. 
For each of the 100 imputed datasets, the endpoint will be compared between ISIS 678354 treatment 
groups and pooled placebo using an ANCOVA model for continuous endpoints or logistic regression 
for binary endpoints as described in the primary analysis for each endpoint. The estimates from the 
100 fitted models will be combined to provide an overall estimate with corresponding confidence 
intervals and p-value (Little & Rubin 2002) 
The following pseudo SAS code will be used to estimate corresponding confidence intervals and 
p-value: 
   proc mianalyze data=diff; 
      modeleffects estimate; 
      stderr stderr; 
   run; 
For the continuous endpoints, the treatment difference and the corresponding 95% CI will be 
presented.  For the analyses using logistic regression, the odds ratio and the corresponding 95% CI 
will be presented.  
Missing values at Months 3 and 12 and other lipid parameters will be imputed in a similar way to the 
primary analysis time point. 
Only observed lipid data will be displayed in the data listings. 
4.9.1.3. 
Multiplicity 
To control the overall Type I error rate at 0.05 across the primary endpoints and secondary endpoints 
for the final analysis, the gatekeeping testing strategy will be applied to the primary endpoint family 
and secondary endpoint family. The hierarchical testing procedure will be utilized within the primary 
endpoint family and secondary endpoint family.  
For the primary endpoint family, the 2 treatment arms will be compared against pooled placebo using 
the hierarchical testing procedure, in which the ISIS 678354 80 mg treatment group will be compared 
to the pooled placebo at the 2-sided alpha level of 0.05, if the comparison is statistically significant 
(p < 0.05), then the ISIS 678354 50-mg treatment group is compared against the pooled placebo at 
the alpha level of 0.05. If the comparison of the ISIS 678354 80-mg treatment group is not statistically 
significant, then the comparison of the ISIS 678354 50-mg treatment group against pooled placebo 
and all secondary endpoints will be considered exploratory.   
Testing of secondary endpoint family will be performed only if the comparison of the primary 
endpoint is statistically significant (p < 0.05) for both ISIS 678354 80-mg and 50-mg treatment 
groups. Testing of the secondary endpoint family will be conducted according to the following 
sequence: 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 31 of 72 
• Secondary endpoint 1: comparison of percent change in fasting TG from Baseline to 
Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 2: comparison of percent change in fasting apoC-III from Baseline to 
the primary analysis time point between ISIS 678354 80-mg treatment group and pooled 
placebo in FAS 
• Secondary endpoint 3: comparison of percent change in fasting apoC-III from Baseline to 
Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 4:  comparison of proportion of patients who achieve ≥ 40% reduction 
in fasting TG from Baseline to the primary analysis time point between ISIS 678354 
80-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 5: comparison of percent change in fasting apoB-48 from Baseline to 
the primary analysis time point between ISIS 678354 80-mg treatment group and pooled 
placebo in FAS 
• Secondary endpoint 6: comparison of percent change in fasting non-HDL-C from Baseline 
to the primary analysis time point between ISIS 678354 80-mg treatment group and pooled 
placebo in FAS 
• Secondary endpoint 7: comparison of percent change in fasting TG from Baseline to 
Month 12 between ISIS 678354 50-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 8: comparison of percent change in fasting apoC-III from Baseline to 
the primary analysis time point between ISIS 678354 50-mg treatment group and pooled 
placebo in FAS 
• Secondary endpoint 9: comparison of percent change in fasting apoC-III from Baseline to 
Month 12 between ISIS 678354 50-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 10: comparison of proportion of patients who achieve ≥ 40% 
reduction in fasting TG from Baseline to the primary analysis time point between 
ISIS 678354 50-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 11: comparison of percent change in fasting apoB-48 from Baseline 
to the primary analysis time point between ISIS 678354 50-mg treatment group and pooled 
placebo in FAS 
• Secondary endpoint 12: comparison of percent change in fasting non-HDL-C from 
Baseline to the primary analysis time point between ISIS 678354 50-mg treatment group 
and pooled placebo in FAS  
• Secondary endpoint 13: comparison of adjudicated acute pancreatitis event rate from 
Week 1 to Week 53 between pooled ISIS 678354 treatment group and pooled placebo in 
the subset of FAS with a prior history of pancreatitis within 10 years prior to Screening 
• Secondary endpoint 14: comparison of adjudicated acute pancreatitis event rate from 
Week 1 to Week 53 between pooled ISIS 678354 treatment group and pooled placebo in 
FAS  
• Secondary endpoint 15: comparison of adjudicated acute pancreatitis event rate from 
Week 13 to Week 53 between pooled ISIS 678354 treatment group and pooled placebo in 
the subset of FAS with a prior history of pancreatitis within 10 years prior to Screening 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 32 of 72 
• Secondary endpoint 16: comparison of adjudicated acute pancreatitis event rate from 
Week 13 to Week 53 between pooled ISIS 678354 treatment group and pooled placebo in 
the FAS 
• Secondary endpoint 17: comparison of proportion of patients who achieve ≥ 70% 
reduction in fasting TG from Baseline to the primary analysis time point between 
ISIS 678354 80-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 18: comparison of percent change in fasting non-HDL-C from 
Baseline to Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in 
FAS 
• Secondary endpoint 19: comparison of percent change in fasting apoB-48 from Baseline 
to Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 20: comparison of proportion of patients who achieve fasting 
TG ≤ 880 mg/dL at the primary analysis time point between ISIS 678354 80-mg treatment 
group and pooled placebo in the FAS 
• Secondary endpoint 21: comparison of proportion of patients who achieve ≥ 70% 
reduction in fasting TG from Baseline to the primary analysis time point between 
ISIS 678354 50-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 22: comparison of percent change in fasting non-HDL-C from 
Baseline to Month 12 between ISIS 678354 50-mg treatment group and pooled placebo in 
FAS 
• Secondary endpoint 23: comparison of percent change in fasting apoB-48 from Baseline 
to Month 12 between ISIS 678354 50-mg treatment group and pooled placebo in FAS 
• Secondary endpoint 24: comparison of proportion of patients who achieve fasting 
TG ≤ 880 mg/dL at the primary analysis time point between ISIS 678354 50-mg treatment 
group and pooled placebo in the FAS 
• Secondary endpoint 25: comparison of adjudicated acute pancreatitis event rate from 
Week 1 to Week 53 between pooled ISIS 678354 treatment group and pooled placebo in 
the subset of FAS with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment 
• Secondary endpoint 26: comparison of adjudicated acute pancreatitis event rate from 
Week 13 to Week 53 between pooled ISIS 678354 treatment group and pooled placebo in 
the subset of FAS with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to 
enrollment 
• Secondary endpoint 27: comparison of proportion of patients who achieve fasting 
TG ≤ 500 mg/dL at the primary analysis time point between ISIS 678354 80-mg treatment 
group and pooled placebo in FAS 
• Secondary endpoint 28: comparison of proportion of patients who achieve fasting 
TG ≤ 500 mg/dL at the primary analysis time point between ISIS 678354 50-mg treatment 
group and pooled placebo in FAS 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 33 of 72 
If the comparison of the first secondary endpoint is statistically significant (p < 0.05), then the second 
secondary endpoint will be tested. However, if the comparison of the first secondary endpoint is not 
statistically significant, then all endpoints of lower rank will be considered exploratory. This process 
is repeated with each subsequent secondary endpoint. 
4.9.1.4. 
Interim Analyses 
There is no interim analysis planned for the study. 
4.9.1.5. 
Examination of Subgroups 
To evaluate the consistency of analysis results in the primary endpoint over parameters such as 
demographic and baseline characteristics, exploratory subgroup analyses will be performed if 
supported by data.  The subgroups include but not limited to:  
• Gender: Male, Female 
• Prior history of pancreatitis within 10 years prior to Screening: Yes vs. No 
• Previous treatment with Volanesorsen: Yes vs. No 
• Region: North America, Europe (including United Kingdom), United States 
• Age: < 65 years, ≥ 65 years  
• Race: White vs. non-White 
• Ethnicity: Hispanic or Latino vs. Not Hispanic or Latino 
• Diabetic status: No vs. Type I or Type II 
• Baseline TG: < median vs. ≥ median 
4.9.2. 
Primary Efficacy Variable  
The primary efficacy analysis will take place after the last patient has completed the Week 53/ET 
visit and the database has been locked, and will be based on the percent change from Baseline in 
fasting TG at primary analysis time point. 
The primary endpoint is the percentage change in fasting TG from Baseline to the primary analysis 
time point. The primary analysis of the primary endpoint is to compare the percent change from 
Baseline to the primary analysis time point in fasting TG between each ISIS 678354 treatment group 
(ISIS 678354 80 mg, ISIS 678354 50 mg) vs. pooled placebo using an ANCOVA model in the FAS.  
The ANCOVA model will use precent change from Baseline to the primary analysis time point in 
fasting TG as dependent variable, the two randomization stratification factors, prior history of 
pancreatitis within 10 years prior to Screening (yes vs. no), previous treatment with Volanesorsen 
(yes vs. no) and treatment group (ISIS 678354 80 mg, ISIS 678354 50 mg, placebo) as the fixed 
effects and nature log-transformed baseline fasting TG as a covariate. To account for potential 
heterogeneity in variance, the 95% CIs will be calculated using the robust variance estimator based 
on the Bell and McCaffrey method (Imbens & Kolesár 2016). 
If patients have intercurrent event(s) before Week 23, 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.  
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 34 of 72 
Patients with missing TG value at the baseline and/or primary analysis time point will have fasting 
TG value multiply imputed using the multiple imputation methods described in Section 4.9.1.2 in the 
SAP. The are provided in the table below: 
Table 1: 
Attributes and Description of the Estimands 
Treatments 
ISIS 678354 80 mg  
Pooled placebo 
Participant 
Population 
Patients with FCS as defined by protocol eligibility criteria 
Variable 
Percent change from Baseline to primary analysis time point (average of 
Weeks 23, 25 and 27) in fasting TG 
Intercurrent events 
(ICEs) and strategies 
Discontinuation of study treatment prior to Week 23 
Treatment policy strategy 
Disallowed concomitant therapy/procedure prior to Week 23 
Treatment policy strategy 
Population-level 
summary 
Difference in means between ISIS 678354 80 mg and pooled placebo in the FAS 
Description of 
estimand 
The difference in means for percent change from Baseline to the primary analysis 
time point in fasting TG between ISIS 678354 80 mg and pooled placebo 
(regardless of early treatment discontinuation, use of additional medication, or 
change in background or concomitant treatments) in patients with FCS  
 
Treatments 
ISIS 678354 50 mg  
Pooled placebo 
Participant 
Population 
Patients with FCS as defined by protocol eligibility criteria 
Variable 
Percent change from Baseline to primary analysis time point (average of 
Weeks 23, 25 and 27) in fasting TG 
Intercurrent events 
(ICEs) and strategies 
Discontinuation of study treatment prior to Week 23 
Treatment policy strategy 
Disallowed concomitant therapy/procedure prior to Week 23 
Treatment policy strategy 
Population-level 
summary 
Difference in means between ISIS 678354 50 mg and pooled placebo in the FAS 
Description of 
estimand 
The difference in means for percent change from Baseline to the primary analysis 
time point in fasting TG between ISIS 678354 50 mg and pooled placebo 
(regardless of early treatment discontinuation, use of additional medication, or 
change in background or concomitant treatments) in patients with FCS  
 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 35 of 72 
The sample SAS code for the ANCOVA model can be found below: 
*************************************************************************** 
* Note:  
*     baseline = baseline TG 
*      impute = the iteration number in the multiple imputation 
*     TRTN = Treatment group: 0=Placebo, 1= ISIS 678354 50 mg, 2 = ISIS 678354 80 mg 
*      PANCR = Prior history of pancreatitis within 10 years prior to Screening: 0 = No, 1 = 
Yes 
*      VOLAN= Previous treatment with Volanesorsen: 0= No, 1= Yes   
*      BM_stderr= Bell and McCaffrey standard error 
*************************************************************************** 
   data TG; set TG; 
      LOGBASE = LOG(baseline);   /* log transformed baseline*/       
 
   proc mixed data = TG; 
      by _impute; 
      class TRTN PANCR VOLAN; 
      model PCHG = TRTN PANCR VOLAN LOGBASE; 
      lsmeans TRTN/e diff cl; 
      estimate ‘ISIS 678354 50 mg vs Placebo’ TRTN -1 1 0;  
      estimate ‘ISIS 678354 80 mg vs Placebo’ TRTN -1 0 1; 
   run; 
The estimates from the fitted models for each of the 100 imputed datasets will be combined to 
provide an overall estimate with corresponding confidence intervals and p-value (Little & Rubin 
2002). The following pseudo SAS code will be used to estimate corresponding confidence intervals 
and p-value: 
   proc mianalyze data=diff; 
      modeleffects estimate; 
      stderr BM_stderr; 
   run; 
The following sensitivity analyses of the primary endpoint will be conducted to assess the 
robustness of the primary analysis result. 
Sensitivity Analysis 1: PPS 
The primary efficacy analysis with ANCOVA model for percent change in fasting TG from Baseline 
to the primary analysis time point described above will be repeated in the PPS. 
Sensitivity Analysis 2: Completer Set (Subset of FAS) 
The primary efficacy analysis with ANCOVA model for percent change in fasting TG from Baseline 
to the primary analysis time point will be repeated in the subset of the patients in the FAS with no 
missing TG values at the primary analysis time point. 
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Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
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Page 36 of 72 
Sensitivity Analysis 3: Exploring the robustness of the primary analysis (FAS) 
Additional sensitivity analyses using different imputation approach with ANCOVA model will be 
conducted in the FAS to assess the robustness of the primary analysis results.  
1. Patients with missing TG value at the primary analysis time point will be imputed using a 
pattern mixture model. Specifically, for patients treated with ISIS 678354 who discontinue 
the treatment due to AE or lack of efficacy (i.e., informative missing), their missing fasting 
TG data after  the last dosing date 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 withdrawal 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 treatment group.  
2. All patients treated with ISIS 678354 will have missing TG values after the last dosing date 
multiply using the CIR approach based on the estimates from the placebo patients. Missing 
TG values for placebo patients will be imputed based on the distribution of the placebo 
group. 
Sensitivity Analysis 4: Non-parametric analysis with Wilcoxon rank-sum test (FAS) 
A nonparametric Wilcoxon rank-sum test will be performed on the percent change in fasting TG from 
baseline to the primary analysis timepoint in the FAS. Missing data will be handled using the same 
multiple imputation method as the primary analysis. The estimates 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 each ISIS 678354 treatment groups group and the pooled placebo 
group. 
Sensitivity Analysis 5: Tipping point analysis (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 4.9.1.2 in the SAP: 
1. For the placebo group, a positive constant shift (δc) will be added to or subtracted from percent 
change of the imputed TG values at the primary time point. The shift will be gradually 
increased 
2. For each value of the placebo shift parameter, a positive constant shift (δt) will be added to or 
subtracted from percent change of the 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 4.9.1.2 in the SAP  
5. Steps 1 to 4 will be repeated with different values of the shift parameters until the tipping 
points are reached. 
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Page 37 of 72 
Values of δc and δt will be determined post-hoc in order to define reasonable increments. 
Sensitivity Analysis 6: ANCOVA model using log-transformed data (FAS) 
The percent change from Baseline to the primary analysis time point in fasting TG between each 
ISIS 678354 treatment group (ISIS 678354 80 mg, ISIS 678354 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 primary analysis time point, x is the baseline value of fasting TG; and the two randomization 
stratification factors and treatment group as factors 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 95% 
confidence intervals (CIs). 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 the baseline 
and/or primary analysis time point will have TG value multiply imputed using the multiple imputation 
methods described in Section 4.9.1.2 in the SAP.  
Descriptive statistics and other data presentation 
Descriptive statistics and cumulative distribution curves will be provided for observed fasting TG 
levels and percent change in fasting TG in each treatment group for the primary endpoint. 
4.9.3. 
Secondary Efficacy Variables 
In order to control the type I error, a sequential closed testing procedure will be employed with the 
sequence of endpoints defined as in Section 4.9.1.3 above. Testing of secondary endpoints will be 
performed only if the treatment comparison of the primary analysis of the primary endpoint is 
statistically significant (p < 0.05) for both ISIS 678354 80-mg and 50-mg treatment groups. Testing 
of the secondary endpoints will be conducted according to the following sequence: if the primary 
analysis of the first secondary endpoint (comparison of percent change in fasting TG from Baseline 
to Month 12 between ISIS 678354 80-mg treatment group and pooled placebo in FAS) is statistically 
significant (p < 0.05) then the second secondary endpoint (comparison of percent change in fasting 
apoC-III from Baseline to the primary analysis time point between ISIS 678354 80-mg treatment 
group and pooled placebo in FAS) will be tested. However, if the treatment comparison based on the 
first secondary endpoint is not statistically significant, then all endpoints of lower rank will be 
considered exploratory. This process is repeated with each subsequent secondary endpoint. 
4.9.3.1. 
Percentage Change from Baseline in Fasting TG at Month 12 
The percent change in fasting TG from Baseline to Month 12 in the FAS will be analyzed in the same 
way as the primary analysis of the primary endpoint. The intercurrent events will be handled using 
the Treatment Policy strategy. 
A 2-dimensional tipping-point analysis will be conducted in the FAS as a sensitivity analysis.  
Descriptive statistics and cumulative distribution curves will be provided for observed fasting 
TG levels and percent change in TG in each treatment group at Month 12. 
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Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
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Page 38 of 72 
4.9.3.2. 
Proportion of Patients who Achieve ≥ 40% Reduction in Fasting TG from Baseline 
at the Primary Analysis Time Point   
The proportion of patients who achieve ≥ 40% reduction in fasting TG from Baseline to the primary 
analysis time point in the FAS will be compared between each ISIS 678354 treatment group and 
placebo group using a logistic regression model with the 2 randomization stratification factors and 
treatment group as the factors, and nature 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. The estimates from the fitted model for each of the 100 imputed datasets will be 
combined to provide an overall odds ratio with corresponding confidence intervals and p-value. 
The intercurrent events will be handled using the Treatment Policy strategy. 
Sensitivity Analysis 1: An additional analysis will be conducted in the FAS, in which all patients who 
have missing data and discontinue treatment before Week 23 will be considered as non-responders. 
Sensitivity Analysis 2: A 2-dimensional tipping-point analysis will be conducted in the FAS using 
the imputed data based on the primary imputation approach as described in Section 4.9.1.2 in the 
SAP. 
4.9.3.3. 
Percentage Change from Baseline in Fasting apoC-III, apoB-48, and non-HDL-C at 
Primary Analysis Time Point (Months 6) and Month 12 
The percent change in fasting apoC-III, apoB-48, and non-HDL-C from Baseline to the primary 
analysis time point and Month 12 in the FAS will be analyzed in the same way as the primary analysis 
of the primary endpoint. The same multiple imputation method as the primary analysis of the primary 
endpoint will be used for imputing missing data. The intercurrent events will be handled using the 
Treatment Policy strategy. A 2-dimensional tipping-point analysis will be conducted in the FAS as a 
sensitivity analysis for each parameter. 
4.9.3.4. 
Proportion of Patients who Achieve Fasting TG ≤ 880 mg/dL at Primary Analysis 
Time Point  
The proportion of patients who achieve fasting TG ≤ 880 mg/dL at the primary analysis time point 
will be analyzed in the same way as the proportion of patients who achieve ≥ 40% reduction in fasting 
TG. Missing TG values will be imputed using the same multiple imputation method as the primary 
analysis of the primary endpoint. The analysis will be conducted in the subset of FAS with baseline 
fasting TG > 880 mg/dL. The intercurrent events will be handled using the Treatment Policy strategy. 
Sensitivity Analysis 1: An additional analysis will be conducted in the subset of FAS with baseline 
fasting TG > 880 mg/dL, in which all patients who have missing data and discontinue treatment before 
Week 23 will be considered as non-responders. 
Sensitivity Analysis 2: A 2-dimensional tipping-point analysis will be conducted in the subset of FAS 
with baseline fasting TG > 880 mg/dL using the imputed data based on the primary imputation 
approach as described in Section 4.9.1.2 in the SAP. 
4.9.3.5. 
Adjudicated Acute Pancreatitis Event Rate from Week 1 to Week 53 in the Subset 
of FAS with a prior history of pancreatitis within 10 years prior to Screening  
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 Acute Pancreatitis Adjudication Committee (PAC) Charter. 
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 
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5) no diagnosis of acute pancreatitis. In the event of any discrepancies between the categories in this 
SAP and the final data transfer, the categories in the final data transfer will be used. 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 number and percentage of subjects and the 
number of events within each classification, by each adjudicator and by final adjudication committee 
respectively, will be summarized. In addition, the number and percentage of cases where the 
adjudicator’s individual categorization of the event was discordant will be provided. The summaries 
be conducted in the FAS. 
The adjudicated acute pancreatitis event rate from Week 1 to Week 53 in the subset of FAS with a 
prior history of pancreatitis within 10 years prior to Screening will be compared between pooled 
ISIS 678354 treatment and placebo group using a Negative Binomial regression model with the 
treatment group and previous treatment with volanesorsen (yes/no) as the factors, and number of 
adjudicated acute pancreatitis events in 5 years prior to the enrollment, i.e., events occurred within 
1826 days (calculated by 365.25 times 5 and rounded to integer) before the first dose date and up to 
the first dose date and time, as a covariate. The logarithm of time in year that each patient was 
observed from Week 1 to Week 53 will be used as an offset variable. From the models, the least 
squares mean rate and standard error for each treatment group as well as, the mean rate ratio relative 
to the placebo group and corresponding 95% confidence intervals 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 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. 
The sample SAS code for the ANCOVA model can be found below: 
*       TRTN = Treatment group: 0=Placebo, 1= ISIS 678354 50 mg or ISIS 678354 80 mg 
*       VOLAN= Previous treatment with Volanesorsen: 0= No, 1= Yes   
*       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);   /* log transformed time*/ 
   proc genmod data = pan; 
      class TRTN VOLAN; 
      model NUMEVENT = TRTN VOLAN NUM5YEAR/dist=negbin link = log 
                       offset = logtime; 
      lsmeans TRTN/diff cl exp ilink; 
   run; 
If the Negative Binomial regression model does not converge, a Poisson regression model with 
Pearson chi-square scaling of standard errors to account for potential overdispersion will be used 
instead of the Negative Binomial regression model. The model will include the same factors and 
covariate as the Negative Binomial regression model.   
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Statistical Analysis Plan 
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Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 40 of 72 
If one treatment group has no event, instead of using Negative Binomial or Poisson regression model 
on the number of events, the proportion of patients with adjudicated acute pancreatitis will be 
compared between pooled ISIS 678354 treatment group and placebo group using a Fisher’s Exact 
test. The odds ratio, corresponding 95% CI, and p-value will be reported.  
Additional dot plots by treatment group will be provided for pancreatitis attacks, grouped by number 
of previous attacks in the last 5 years.  
4.9.3.6. 
Adjudicated Acute Pancreatitis Event Rate from Week 1 to Week 53 in the FAS 
The data will be analyzed in the same way as described in Section 4.9.3.5. 
Additional dot plots will be by treatment group provided for pancreatitis attacks, grouped by number 
of previous attacks in the last 5 years.  
4.9.3.7. 
Adjudicated Acute Pancreatitis Event Rate from Week 13 to Week 53 in the Subset 
of FAS with a prior history of pancreatitis within 10 years prior to Screening  
The data will be analyzed in the same way as described in Section 4.9.3.5.  
4.9.3.8. 
Adjudicated Acute Pancreatitis Event Rate from Week 13 to Week 53 in the FAS 
The data will be analyzed in the same way as described in Section 4.9.3.5. 
4.9.3.9. 
Adjudicated Acute Pancreatitis Event Rate from Week 1 to Week 53 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. The period of 5 years 
prior to enrollment spans from 1826 days before the first dose date and up to the first dose date and 
time. 
4.9.3.10. Adjudicated Acute Pancreatitis Event Rate from Week 13 to Week 53 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.  
4.9.3.11. Proportion of Patients who Achieve Fasting TG ≥ 70% Reduction from Baseline at 
Primary Analysis Time Point 
The proportion of patients who achieve fasting TG ≥ 70% reduction at the primary analysis time point 
in the FAS will be analyzed in the same way as the proportion of patients who achieve 
≥ 40% reduction in fasting TG. Missing TG values will be imputed using the same multiple 
imputation method as the primary analysis of the primary endpoint. The intercurrent events will be 
handled using the Treatment Policy strategy. 
Sensitivity Analysis 1: An additional analysis will be conducted in the FAS, in which all patients who 
have missing data and discontinue treatment before Week 23 will be considered as non-responders. 
Sensitivity Analysis 2: A 2-dimensional tipping-point analysis will be conducted in the FAS using 
the imputed data based on the primary imputation approach as described in Section 4.9.1.2 in the 
SAP. 
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Project Document Effective Date: 15 Aug 2023 
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Page 41 of 72 
4.9.3.12. Proportion of Patients who Achieve Fasting TG ≤ 500 mg/dL at Primary Analysis 
Time Point  
The proportion of patients who achieve fasting TG ≤ 500 mg/dL at the primary analysis time point 
will be analyzed in the same way as the proportion of patients who achieve ≥ 40% reduction in fasting 
TG. Missing TG values will be imputed using the same multiple imputation method as the primary 
analysis of the primary endpoint. The analysis will be conducted in the subset of FAS with baseline 
fating TG > 500 mg/dL. The intercurrent events will be handled using the Treatment Policy strategy. 
Sensitivity Analysis 1: An additional analysis will be conducted in the subset of FAS with baseline 
fasting TG > 500 mg/dL, in which all patients who have missing data and discontinue treatment before 
Week 23 will be considered as non-responders. 
Sensitivity Analysis 2: A 2-dimensional tipping-point analysis will be conducted in the subset of FAS 
with baseline fasting TG > 500 mg/dL using the imputed data based on the primary imputation 
approach as described in Section 4.9.1.2 in the SAP. 
4.10. 
Safety Evaluation 
All safety summaries and analyses will be based upon the Safety Set as defined in Section 4.5. 
Risk difference and corresponding 95% CI in the crude incidence rates between each active 
treatment group (or total ISIS 678354) and pooled placebo group in selected safety endpoint will be 
provided. The crude incidence rate (or 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 Miettinen-Nurminen (MN) method.  
4.10.1. 
Extent of Exposure  
The exposure to treatment will be presented in terms of the duration of exposure (in days), number 
of doses administered, and amount of Study Drug received for each patient. The duration of exposure 
will be calculated as the last dose date minus the first dose date plus 28 days (one dose interval) for 
each patient. Treatment duration, number of doses, and amount of Study Drug received will be 
summarized by treatment group.   
Compliance with Study Drug administration will be summarized by descriptive statistics by treatment 
group. 
The evaluation of compliance of ISIS 678354 will be done using the following formula: 
 
Actual total dose injected (mg) *100/Expected total dose (mg) to be administered.  
The evaluation of compliance of placebo will be done using the following formula: 
Actual total volume injected (mL) *100/Expected total volume (mL) to be administered. 
Patients in Cohort A will receive 50 mg of ISIS 678354 once every 4 weeks or matching volume of 
placebo (0.5 mL) Weeks 1-49 of the Treatment Period. Patients in Cohort B will receive 80 mg 
ISIS 678354 once every 4 weeks or matching volume of placebo (0.8 mL) Weeks 1-49 of the 
Treatment Period.  
For early withdrawals/terminations, the total dose injected will be calculated for the period up to 
their withdrawal/termination. 
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The following summaries will be provided: 
• A summary of the duration, number of doses administered and the total amount of study 
drug by treatment group 
• A summary of percent compliance by treatment group. 
• Number of patients with dose interruption due to AE and number of patients with study drug 
reduced due to AE. 
• A 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 
All adverse events will be coded by the MedDRA coding system. The final version used will be 
designated in the clinical study report.   
The following imputation rules will be applied to impute start dates under conservative principles: 
• If year, month and day are all missing then assign the date of 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 
o after the month-year of the first dose of Study Drug then assign the first day of the 
month 
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. 
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An adverse event will be regarded as treatment emergent if it is present prior to receiving the first 
dose of study drug and subsequently worsens, or is not present prior to receiving the first dose of 
study drug but subsequently appears. 
In addition, if the 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” AE records will be identified based on the AE start 
date. AE start date of the second record will be the AE stop date of first record. These linked events 
should be compared pairwise. Consider the following two cases, where the AE severity 
(mild/moderate/severe) and seriousness (Yes/No) between the two records in a pair are compared. 
Case 1:  The first AE record in the pair occurs before the first dosing, and the second AE 
record occurs after the first dosing.   
If the AE severity or seriousness 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 is considered as a TEAE.  
• The frequency of patients with any incidence of AEs and the number events will be 
summarized by MedDRA preferred term and system organ class for: 
• Any TEAE 
• TEAEs potentially related to Study Drug. Related is defined as “Related”, “Possible”, or 
missing relationship to Study Drug 
• Any treatment-emergent adverse event by severity. At each level of patient 
summarization, a patient is classified according to the worst reported severity if the 
patient reported one or more events. Adverse events with missing severity will be 
categorized as “Missing” for this summary. 
• TEAEs potentially related to Study Drug by severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to death 
• Serious TEAEs 
• Serious TEAEs potentially related to Study Drug 
• TEAE with an incidence rate > 5% in any treatment groups  
• Non-serious TEAE with an incidence rate > 5% in any treatment groups  
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Adverse event summaries will be presented alphabetically by SOC and preferred term (PT) and by 
descending frequency. An overview of AEs will be provided for all TEAes. AEs that lead to treatment 
discontinuation, and AEs that lead to death will be listed.   
In addition, a summary of adjudicated AEs will be provided for pancreatitis and MACE separately.  
Adjudicated events will also be listed. 
4.10.3. 
Adverse Events of Special Interest 
The following events are considered AE of special interest and will be summarized: 
•  Platelet count reduction to levels below 50,000/mm3 accompanied by a major bleeding 
event (MB) or clinically relevant non-major bleeding (CRNMB) event or platelet count 
reduction to levels below 25,000/mm3, irrespective of bleeding status  
• 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. 
The number and percentage of patients experiencing events as well as the total number of reported 
events, classified by SOC and PT, will be tabulated by treatment group. 
The following additional analyses may be provided if supported by data: 
• A cumulative incidence plot  
• Risk difference and its 95% CI in the crude incidence rates between each active 
treatment group (or total ISIS 678354) and pooled placebo group. The analysis methods 
are detailed in Section 4.10 of this SAP. 
• Exposure adjusted incidence rates (EAIRs) and risk difference (or ratio) in EAIRs may 
also be provided, if deemed necessary. EAIR is defined as the number of patients who 
experienced at least one event times 100 divided by total patient-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 (i.e., last participation date minus first dose date plus one day divided by 365.25). 
• Exposure adjusted event rates (EAERs), defined as the number of events times 100 
divided by the total duration in the on-study period in year. 
4.10.4. 
Other Events of Interest 
4.10.4.1. Local Cutaneous Reactions at the Injection Site 
Local cutaneous reaction at injection site (LCRIS) is defined as (A) moderate or severe adverse events 
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 two 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 using the MedDRA coding system, by PT and 
by treatment group. Patients with moderate, severe and any LCRIS will also be summarized. 
Discontinuations due to AE at the injection site will be summarized separately. 
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Percentage of injections leading to LCRIS will be summarized by PT and overall using the descriptive 
statistics. Additionally, percentage of injections leading to events will be summarized by moderate, 
severe severity and overall discontinuation of Study Drug due to AE at injection site.  
Percentage of injections leading to LCRIS will be calculated as follows for each patient: (A/B)*100, 
where A = number of injections with a 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 will be summarized descriptively by treatment group and total 
ISIS 678354 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, time to onset of the first event, the number of 
injections prior to the first LCRIS will also be summarized descriptively by treatment group and total 
ISIS 678354 treated. 
LCRIS will also be listed. 
4.10.4.2. 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 two days (i.e., event resolution date not on the day of the event onset date or 
the day after) or ongoing. ISR will be summarized using the MedDRA coding system, by PT and by 
treatment group.  
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 will be summarized descriptively by treatment group and total 
ISIS 678354 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 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, time to onset of the first event, the number of injections 
prior to the first ISR will also be summarized descriptively by treatment group and total ISIS 678354 
treated. 
ISR will also be listed. 
4.10.4.3. Flu-like Reactions 
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. 
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Definition 2 (FLR 2): defined as adverse events with PTs including either (A) Influenza like illness 
or (B) Pyrexia or Feeling hot or Body temperature increased, plus at least two of the following 
symptoms with the PTs: Chills, Myalgia, or Arthralgia, starting on day of injection or the next day. 
Flu-like reactions will also be summarized using the MedDRA coding system, by preferred term and 
by treatment group. 
Percentage of injections leading to flu-like reactions will be summarized by treatment group using 
the descriptive statistics. 
Percentage of the injections leading to flu-like reactions will be calculated as follows for each patient: 
(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. 
Flu-like reactions will also be listed. 
4.10.4.4. Bleeding TEAE  
Bleeding TEAEs will be analyzed for the following categories. The number and percentage of 
patients experiencing events as well as the number of reported events, classified by SOC and PT, 
will be tabulated by treatment group. The risk different (95% CI) in the crude incidence rates 
between each active treatment group (or total ISIS 678354) and pooled placebo group will be 
provided. 
• 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 
• Clinical bleeding events with concomitant anticoagulant or antiplatelet medication 
• Clinical bleeding events without concomitant anticoagulant or antiplatelet medication 
4.10.4.5. Thrombocytopenia TEAE  
The number and percentage of patients experiencing events as well as the number of reported events, 
classified by PT, will be tabulated by treatment group. The risk different (95% CI) in the crude 
incidence rates between each active treatment group (or total olezarsen) and pooled placebo group 
will be provided. 
• Thrombocytopenia TEAE (defined based on the ‘Thrombocytopenias’ High Level 
Terms [HLT] or ‘Platelet count decreased’ PT) 
4.10.4.6. Hypersensitivity TEAE  
Hypersensitivity TEAEs will be analyzed for the following categories. The number and percentage 
of patients experiencing events will be tabulated by treatment group. The risk difference (and 95% 
CI) in the crude incidence rates between each active treatment group (or total ISIS 678354) and pooled 
placebo group will also be provided.  
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• 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) by PT  
• Serious TEAEs, fatal TEAEs and TEAEs leading to treatment discontinuation in 
Hypersensitivity FMQ (broad) by PT  
• Action taken with drug due to TEAEs in the Hypersensitivity FMQ (broad)  
• Rescue medication used in management TEAEs in Hypersensitivity FMQ (broad)  
• 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 
will be provided. 
4.10.4.7. Renal Impairment TEAE  
Renal impairment TEAEs will be analyzed for the following categories. The number and percentage 
of patients experiencing events will be provided. The risk different (95% CI) in the crude incidence 
rates between each active treatment group (or total ISIS 678354) and pooled placebo group will be 
provided.  
• Renal impairment TEAEs (defined based on the ‘Acute renal failure’ SMQ (narrow and 
broad)) 
• 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 
For patients who had 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. 
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For patients who had 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 data listing including eGFR and serum creatinine and a 
graphical patient profile will be provided. 
4.10.4.8. Abnormal Liver Function TEAE 
Abnormal liver function TEAEs will be analyzed for the following categories. The number and 
percentage of patients experiencing events tabulated by treatment group. The risk difference (95% 
CI) in the crude incidence rates between each active treatment group (or total ISIS 678354) and pooled 
placebo group will be provided. 
• Abnormal liver function TEAE (defined based on the ‘Drug related hepatic disorders – 
comprehensive search’ SMQ (narrow and broad))  
• TEAEs, Serious TEAEs, drug-related TEAEs, fatal TEAEs and TEAEs leading to 
treatment discontinuation in Hepatic Injury and Hepatic Failure FMQ (narrow) 
• TEAEs in Hepatic Injury and Hepatic Failure FMQs (narrow) by PT  
• Discontinuations and Lost to follow-up with Liver Safety Lab Elevation or AEs (in 
Hepatic FMQs) 
4.10.5. 
Clinical Laboratory Evaluation 
The following is the list of safety lab analytes that will be collected throughout the study: 
• Chemistry: 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, and GGT. 
• Hematology: red blood cells, hemoglobin, hematocrit, MCV, MCH, MCHC, RDW, 
platelets, white blood cells (WBCs), and WBC differential in both percentage and 
absolute count (neutrophils, eosinophils, basophils, lymphocytes, and monocytes) 
• Coagulation: aPTT, PT, international normalized ratio (INR) 
• Other assessments: hs-CRP (inflammatory), HOMA-IR, fructosamine, glycated 
hemoglobin (HbA1c), glycated albumin  
• Screening Tests: hepatitis B surface antigen, hepatitis C antibody, HIV antibody, FSH 
(women), serum βhCG (women). The screening test data will only be displayed in 
patient listings 
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• Urinalysis: color, appearance, specific gravity, pH, protein, blood, ketones, urobilinogen, 
glucose, bilirubin, leukocytes esterase, nitrate, and microscopic examination.  The 
expanded urinalysis data will be only displayed in patient listings. Urine 
albumin/creatinine ratio (UACR) and protein/creatinine ratio (UPCR) will be 
summarized.  
All safety lab data will also be displayed in patient listings based on all randomized patients.  
Chemistry, hematology, coagulation, other assessments, selected urinalysis, and selected lipid 
parameters including LDL-C and apoB (result, change and percent change from Baseline) will be 
summarized using descriptive statistics (n, mean, standard error, standard deviation, median, Q1, Q3, 
minimum and maximum) by treatment group and study visit.    
A frequency bar chart of the missing data and existing data at each visit for patients remaining in the 
trial will be provided for creatinine, BUN, total bilirubin, ALT, AST, ALP, estimated Glomerular 
Filtration Rate (eGFR), hsCRP, hemoglobin, hematocrit, platelets, white blood cells, UACR, UPCR. 
Additional analyses of key safety laboratory data 
The following analyses of key safety laboratory data will be provided. 
Hepatobility Laboratory Abnormalities: 
The number and percent of patients falling in each of the following categories based on results after 
first dose will be tabulated by treatment group. The risk different (95% CI) in the crude incidence 
rates between each active treatment group (or total ISIS 678354) and pooled placebo group will be 
provided for selected categories. 
• ALT or AST≥  ULN 
• The higher of ALT/AST ≥ 3 × upper limit of normal (ULN) or ALT/AST ≥ 2 × Baseline 
(i.e., ALT/AST ≥ 3 × ULN and ALT/AST ≥ 2 × Baseline) 
• ALT/AST ≥ 3 × ULN 
• ALT/AST ≥ 5 × ULN 
• ALT/AST ≥ 8 × ULN 
• ALT/AST ≥ 10 × ULN 
• ALT/AST ≥ 20 × ULN 
• Highest ALT falling in: ≥ 3 × ULN - < 5 × ULN,  ≥ 5 × ULN - < 10 × ULN, 
≥ 10 × ULN -< 20 × ULN (the risk difference will not be provided for this category) 
•  Total bilirubin ≥ 2 × ULN 
•  Total bilirubin ≥ 5 × ULN 
•  Total bilirubin ≥ 8 × ULN 
• ALT or AST ≥ 3 × ULN and Total bilirubin ≥ 2 × ULN 
• ALP ≥ 2 × ULN and (baseline ALP < 2 × ULN or baseline ALP missing) 
• Direct bilirubin ≥ 2 × ULN 
• Direct bilirubin ≥ 5 × ULN 
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• GGT ≥ 2 × ULN 
• ALT ≥ 3 × ULN and INR ≥ 1.5 
• ALP ≥ 2 × ULN 
• ALP ≥ 3× ULN 
• 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 
results after first dose will be tabulated by treatment group (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):  
• The higher of ALT/AST ≥ 3 × ULN or ALT/AST ≥ 2 × Baseline, which is confirmed 
• ALT/AST ≥ 3 × ULN, which is confirmed  
• ALT/AST ≥5 × ULN, which is confirmed  
• ALT/AST ≥10 × ULN, which is confirmed  
• ALT/AST ≥20 × ULN, which is confirmed  
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 at least 2-fold increases from Baseline, spaghetti plots 
and a listing of all of the ALT, AST, total bilirubin, direct bilirubin, INR, and ALP records will be 
provided.  
For patients having elevation in liver enzymes (ALT ≥ 3 × ULN), the time to onset of the first event 
will be summarized using descriptive statistics 
Other liver abnormalities including elevation of ALT (≥ 3 × ULN) accompanied by INR ≥ 1.5, 
elevation of ALT (≥ 3 × ULN) accompanied by elevated total bilirubin ≥ 2 × ULN and 
ALP ≥ 2 × ULN will be reviewed by the study team and summarized if needed.  
Additionally, evaluation of Drug Induced Serious Hepatoxicity (eDISH) plots by treatment group will 
be provided for liver safety parameters (AST, ALT, Total bilirubin and ALP).  
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. The risk different 
(95% CI) in the crude incidence rates between each active treatment group (or total ISIS 678354) and 
pooled placebo group will be provided. 
• Serum creatinine ≥ 0.3 mg/dL higher than baseline 
• Serum creatinine ≥ 50% higher than baseline 
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A listing of the creatinine values over time will be provided for each patient meeting either of the 
two criteria. 
The number and percent of patients falling in each of the following additional categories based on 
results at any time after first dose will also be tabulated by treatment group. The risk different (95% 
CI) in the crude incidence rates between each active treatment group (or total ISIS 678354) and 
pooled placebo group will be provided. 
• Serum creatinine ≥ 2.0 × baseline, and ≥ 3.0 × baseline  
• eGFR reduction from baseline, ≥ 25%,  ≥ 30% , ≥ 50%, and ≥ 75%  
• UACR ≥ 300 mg/g, ≥ 500 mg/g, ≥ 600 mg/g,  ≥ 1200 mg/g 
• UACR increase from Baseline ≥ 50%   
• UPCR ≥ 500mg/g, ≥ 1000 mg/g, ≥ 2000 mg/g 
A listing of creatinine and eGFR will be provided for those patients having ≥ 2-fold elevation above 
baseline in creatinine or ≥ 50% decrease from baseline in eGFR. 
For patients having eGFR ≥ 25% decrease from baseline, the time to onset of the first event will be 
summarized using descriptive statistics. 
Platelet Abnormalities: 
The incidence of patients 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). The risk different (95% CI) in the crude incidence rates between each active 
treatment group (or total ISIS 678354) and pooled placebo group will be provided for selected 
categories. 
• Any 2 occurrences of platelet count < 140,000/mm3 
• Any single occurrence of platelet count < 100,000/mm3  
• Any 2 occurrences of platelet count < 140,000/mm3 or any single occurrence of platelet 
count < 100,000/mm3  
• Worst platelet count falling in: ≥ 140,000/mm3, 100,000/mm3 to < 140,000/mm3, 
75,000 to < 100,000/mm3, 50,000 to < 75,000/mm3, 25,000 to < 50,000/mm3, 
0 to < 25,000/mm3 (the risk difference will not be provided for this category) 
• Worst platelet reduction from Baseline ≥ 30% and ≥ 50%  
The incidence of patients with post-baseline platelets results falling in each of the following 
categories based on confirmed results will also be summarized: 
• Worst platelet count falling in: ≥ 140,000/mm3, 100,000/mm3 to < 140,000/mm3, 
75,000 to < 100,000/mm3, 50,000 to < 75,000/mm3, 25,000 to < 50,000/mm3, 
0 to < 25,000/mm3 (the risk difference will not be provided for this category) 
• Worst platelet reduction from Baseline ≥ 30% and ≥ 50%  
For patients having post-baseline platelet count < 100,000/mm3, the time to onset of the first event 
will be summarized using descriptive statistics 
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The correlation between anti-platelet antibodies and platelet decrease as well as immunogenicity 
status may be explored if supported by data. 
Hypersensitivity Related Analyte Abnormalities: 
The number and percentage of patients falling in each abnormality category outlined below will be 
tabulated by treatment group. The risk different (95% CI) in the crude incidence rates between each 
active treatment group (or total ISIS 678354) and pooled placebo group will be provided for selected 
categories. 
• Eosinophils > 650 cells/uL, > 1500 cells/uL, > 5000 cells/uL 
• WBC > 10,800 cells/uL, > 13,000 cells/uL, > 15,000 cells/uL 
Shift Analysis 
The following hematology and hepatic enzymes lab results will be categorized based on Guidance 
for Industry – Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials (September 2007) and the incidence of shift from Baseline to worst 
post-baseline value taken after the first dose will be summarized. 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”. Number and proportion of patients with shift from baseline to worst 
post-baseline values based on the confirmed results by toxicity category for ALT, AST, and platelets 
will also be tabulated. 
• Hemoglobin:  shift from Baseline to minimum post-baseline value 
• WBCs:  shift from Baseline to minimum post-baseline value  
• WBCs:  shift from Baseline to maximum post-baseline value  
• Platelets:  shift from Baseline to minimum post-baseline value  
• Creatinine:  shift from Baseline to maximum post-baseline value   
• BUN:  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   
Hemoglobin change from baseline to minimum post-baseline value will be summarized by toxicity 
category as well.  
Shift from Baseline to maximum post-baseline value for urinary albumin/creatinine ratio, 
protein/creatinine ratio and LDL-C by treatment group will be provided. The categories for the shift 
table will be:  
• Urinary albumin/creatinine ratio: < 30 mg/g; 30 to < 300 mg/g; ≥ 300 mg/g 
• Urinary protein/creatinine ratio: < 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 to < 190 mg/dL and ≥ 190 mg/dL.   
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4.10.6. 
Vital Signs and Physical Findings  
Vital signs include:  
• pulse rate (beats/minute) 
• systolic and diastolic blood pressure (SBP and DBP) (mmHg) 
• respiration rate (breaths/min) 
• body temperature, measured under the arm pit (°C) 
• weight  
• BMI 
Summary tables will be created to present the descriptive statistics for vital sign values as well as the 
change and percent change from Baseline at each study visit. 
Number and percentage of subjects falling in each of the following categories will be tabulated by 
treatment group: 
• Change from baseline in SBP > 5, > 10, > 15, > 20, > 30 mmHg 
• Change from baseline in DBP > 5, > 10, > 15, > 20, > 30 mmHg 
• Change from baseline in pulse > 5, > 10, > 15, > 20 bpm 
A by-subject listing of vital signs will be provided. 
Adverse changes in physical examinations that are deemed clinically significant by the Investigator 
will be classified as adverse events. Physical examination results will be listed. 
4.10.7. 
12-Lead Electrocardiograms (ECG) 
ECGs will be performed in triplicate at the visits indicated in the protocol Schedule of Procedures. 
The ECG data will include ventricular rate, PR interval, QRS duration, QT, QTc intervals (machine 
reading), QTc interval calculated using Fridericia’s formula (QTcF) and overall interpretation. For 
the continuous variables above, descriptive statistics of the average of triplicate results at each study 
visit, as well as the change and percent change from Baseline to each study visit, will be presented in 
summary tables; for the categorical responses to overall interpretation, the worst of triplicate results 
at each visit will be summarized by counts and percentages. All the data collected in triplicate will be 
listed. Following summary tables will be presented. 
• A summary of each ECG parameter by treatment group and visit 
• A summary of the number and percentage of subjects with QTcF interval exceeding the 
following predefined upper limit: > 450 ms, > 480 ms, > 500 ms. The average of 
triplicates will be used to categorize the data. 
• Shift table from baseline to the worst (highest) post-baseline QTcF interval by treatment 
group. The categories for the shift table will be: ≤ 450 msec, > 450 msec to ≤ 480 msec, 
> 480 msec to ≤ 500 msec, and > 500 msec. The average of triplicates will be used to 
categorize the data. 
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• The number and percent of patients experiencing an increase from baseline in QTcF 
interval of greater than 30 msec or 60 msec at any time post-baseline will be 
summarized by treatment group. This analysis will be presented for all patients in the 
Safety set and also for the subgroup whose QTcF is normal at baseline. Normal QTcF is 
defined as ≤ 450 msec for males or ≤ 470 msec for females. The average of triplicates 
will be used to determine the increase. 
ECG results will be listed. 
4.10.8. 
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 the 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 
During the treatment period, blood samples for the determination of plasma ISIS 678354 
concentrations will be collected from all patients prior to dosing.   
Table 2: 
Plasma Trough and Post-Treatment Sampling Schedule for all Patients 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
3 
5 
9 
13 
17 
21 
25/ET-
L2* 
29 
37 
45 
53/ET-L5* 
or Tx ET 
4** 8** 13/Post 
Tx ET** 
Study 
Day 
1 
15 
29 
57 
85 
113 141 169 
197 
253 
309 
365 
28** 56** 91** 
 
Pre-dose, 
2 hr ± 15 min***, 
and 4 hr ± 30 min*** 
Any 
time  
Pre-
dose 
Pre-
dose 
Pre-dose 
and 2 hr 
± 15 min 
Pre-
dose 
Pre-
dose 
Pre-dose 
and 2 hr 
± 15 min 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Any time 
Any 
time 
Any 
time 
Any time 
* Landmark visit.  For early termination landmark (ET-L) visits:  Week 25 is ET-L2 and Week 53 is ET-L5 
** Weeks/days from end of treatment.  End of treatment is defined as 1 dosing interval post-last dose 
*** Samples can be collected within the ± 15 min and ± 30 min window, but the actual sampling time should be 
recorded accurately in eCRF 
 
Plasma concentrations of ISIS 678354 (measured as total full-length oligonucleotides or 
ISIS 678354-eq, i.e., ISIS 678354-eq, including fully conjugated, partially conjugated, and 
unconjugated ISIS 678354), 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 
treatment, actual dose, gender, subject ID, subject immunogenicity (IM) status and study day. Plasma 
concentrations below the lower limit of quantification (LLOQ) will be presented as “BLQ”. 
In addition, percent differences between scheduled and actual sampling times will also be listed. 
For all patients who receive ISIS 678354 treatment, ISIS 678354 plasma trough (pre-dose), peak (2 hr 
and 4 hr), and post-treatment (28, 56, 84, and 119 days after the last dose) concentrations will be 
summarized using descriptive statistics by treatment, dose, study day, and scheduled time point, with 
and without stratification by IM status (see Section 4.11.2). For the purpose of calculating typical 
descriptive statistics (n, mean, SD, %CV, geometric mean, geometric %CV, median, minimum and 
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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 
(percent difference between scheduled and actual sampling time greater than 30%), or large 
deviations between actual dose and nominal dose (percent difference between nominal 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 ISIS 678354 treatment and not participating in the OLE, 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 IM status 
(see Section 4.11.2). 
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 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-ISIS 678354 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 unevaluable, and when applicable, titer of anti-ISIS-678354 antibodies) before, 
during, and after treatment with study drug (ISIS-678354 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 by treatment and dose 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. Subject Level ADA Data 
Subject ADA status overall (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, a study subject will be assigned ‘Unknown’ ADA status.   
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Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
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Furthermore, subjects 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): 
• 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 
study 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 subject 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. 
• Subject 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 subject 
has Week 1 Day 1 pre-dose sample (baseline) tested as negative; "Unknown" if the subject 
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 positive sample observed, and will be calculated for subjects with treatment-induced 
ADA and treatment-boosted ADA 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 
colleted - first dose date +1. 
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CONFIDENTIAL 
Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 57 of 72 
• 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 subject. 
• 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 subject. 
• Total number of ADA Samples evaluated (NOADASAMT): the total number of ADA 
samples being collected and analyzed successfully with reportable results for the subject. 
Lastly, subjects with positive ADA status may further be classified as being transient or persistent 
ADA response, if there are sufficient number of subjects with transient ADA status. Transient and 
persistent ADA definitions are defined below and based on (Shankar et al. 2014): 
Transient ADA response:  
• 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 
• 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: 
• 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 
• 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 subject 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. Subject level IM parameters 
(as described above), if applicable, will be listed by treatment and dose for all evaluable subjects, 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 PK, PD, efficacy and Safety 
The impact of IM on PK, PD, and safety will be evaluated by stratifying plasma PK exposure 
measures (such as plasma peak, trough and post-treatment ISIS 678354 concentrations, etc.), 
PD biomarker levels, selected clinical efficacy end points and safety measures by subject level ADA 
data, summarized using typical descriptive statistics, and presented graphically and/or in tables. 
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CONFIDENTIAL 
Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 58 of 72 
Efficacy measures to be stratified by subject level ADA data (e.g., ADACAT) will include but may 
not be limited to apoC-III and TG levels. Safety measures to be stratified by subject level ADA data 
will include but may not be limited to AEs, and lab tests for hematology, liver and kidney functions, 
as appropriate.   
Additionally, within subject comparisons on plasma C2h may be conducted in patients with multiple 
C2h concentrations and presented graphically by subject IM status overall and treatment if deemed 
appropriate (Wang et al. 2016) 
Lastly, other stratifications (e.g., based on antibody titer, onset of ADA, subject 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 Analysis 
4.11.3.1. Percent Change in Fasting TG, apoC-III, apoB-48, and non-HDL-C at Month 3 
The following tertiary/exploratory endpoints will be compared between ISIS 678354 treatment 
group (ISIS 678354 80 mg, ISIS 678354 50 mg) and placebo using an ANCOVA model with the 
percent change in original scale as the dependent variable, two stratification factors and treatment 
group as factors, the corresponding log-transformed baseline fasting results as covariates in the 
FAS. The same multiple imputation method as the primary analysis of the primary endpoint will be 
used for imputing missing data. 
• Percent change in fasting TG from Baseline at Month 3  
• Percent change in fasting apoC-III from Baseline at Month 3  
• Percent change in fasting apoB-48 from Baseline at Month 3 
• Percent change in fasting non-HDL-C from Baseline at Month 3 
The change and percent change from Baseline in fasting TG, apoC-III, apoB-48, and non-HDL-C 
will be summarized by treatment group over time. 
4.11.3.2. Treatment Response Rate 
The following treatment response rates between ISIS 678354 treatment group (ISIS 678354 80 mg, 
ISIS 678354 50 mg) and placebo groups will be compared as exploratory analyses using logistic 
regression with the treatment group, two randomization stratification factors as the factors, and nature 
log-transformed baseline fasting TG as a covariate in the FAS.  
• Proportion of patients who achieve fasting TG ≥ 40% Reduction from Baseline at Months 3 
and 12 
• Proportion of patients who achieve fasting TG ≥ 70% Reduction from Baseline at Months 3 
and 12 
• Proportion of patients who achieve fasting TG ≤ 880 mg/dL at Months 3 and 12 in the subset 
of FAS with baseline fasting TG > 880 mg/dL  
• Proportion of patients who achieve fasting TG ≤ 500 mg/dL at Months 3 and 12 in the subset 
of FAS with baseline fasting TG > 500 mg/dL  
Missing values will be handled using the same multiple imputation method as the primary analysis 
of the primary endpoint.   
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
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4.11.3.3. FCS Symptoms 
The FCS Symptoms Questionnaire includes 4 items addressing the severity of abdominal pain, 
physical fatigue, difficulty thinking and diarrhea. These 4 items are administered on a daily basis and 
ask patients to rate the worst severity of each symptom in the past 24 hours using a 0–10 numeric 
rating scale. Higher scores denote more severe symptoms.  
The daily symptom composite score will be calculated as the average of the non-missing scores across 
the 4 symptom items. If two or more questions are missing, the symptom composite score will be 
considered as missing for the day. If one item is missing, then the composite score will be calculated 
as the average of the 3 non-missing item scores 
The data will be mapped to study week based on the visit window specified in Section 4.2.4. The data 
in the visit window will be averaged and used for summary and analysis. In addition to the weekly 
average, the highest (worst) response in each week will also be determined and used for summary 
and analysis. If patients complete less than 4 daily assessments in a week, then the weekly FCS 
symptom scores will be considered as missing for the week. 
Item-level scores and the symptom composite scores, as well as their changes from baseline will be 
summarized by treatment group and by study week over time using descriptive statistics.  
A summary of abdominal pain using the following categories will also be provided: no pain 
(pain score: 0), mild (pain score: > 0 – 3), moderate (pain score: > 3–6), or severe (pain score: > 6-10). 
The frequency and percentage in each category will be tabulated by treatment group and by study 
week over time. 
The change from baseline in the weekly average item and composite scores at the primary analysis 
time point (average of Weeks 23 to 27) and at Month 12 (average of Weeks 49 to 53) as well as 
change from baseline in the highest (worst) item and composite scores at the primary analysis time 
point (worst of Weeks 23 to 27) and at Month 12 (worst of Weeks 49 to 53) will be analyzed using 
an ANCOVA model with the two stratification factors and treatment group as factors and the 
corresponding baseline score as a covariate, and will be conducted in the FAS.   
The analyses described above will also be repeated using the corresponding FCS symptom collected 
at the two-week recall administered the first day of screening as the baseline. 
The following two exploratory analyses will be performed in the subset of FAS patients who reported 
any abdominal pain (pain score > 0) at Baseline: 
1. The first exploratory analysis will be performed to compare the change from Baseline in 
the weekly average abdominal pain scores at the primary analysis time point (average of 
Weeks 23 to 27) and at Month 12 (average of Weeks 49 to 53) between the ISIS 678354 
treatment groups and placebo group in this subset of patients using an ANCOVA model 
with the two stratification factors and treatment group as the factors and baseline average 
abdominal pain score as covariate.   
2. The secondary exploratory analysis will be performed to compare the change from 
Baseline in the highest (worst) abdominal pain score at the primary analysis time point 
(Weeks 23 to 27) and at Month 12 (Weeks 49 to 53) using an ANCOVA model with the 
two stratification factors and treatment group as factors and worst baseline abdominal pain 
score as covariate in this subset.    
In addition to the analyses described above based on the observed data, the missing values will be 
imputed. The change from baseline in the weekly average item and composite scores at the primary 
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Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 60 of 72 
analysis time point and at Month 12 as well as change from baseline in the highest (worst) item and 
composite scores at the primary analysis time point and at Month 12 will be analyzed based on the 
imputed data using an ANCOVA model with the two stratification factors and treatment group as 
factors and the corresponding baseline score as a covariate, and will be conducted in the FAS.   
The missing values will be imputed as follows: 
• For patients with a missing baseline value, their baseline scores will be imputed using 
the average of non-missing data from other patients in the same stratification category. 
There are 4 stratification categories:  
o history of pancreatitis = Yes, previous treatment with Volanesorsen = No  
o history of pancreatitis = Yes, previous treatment with Volanesorsen = Yes  
o history of pancreatitis = No, previous treatment with Volanesorsen = No 
o history of pancreatitis = No, previous treatment with Volanesorsen = Yes 
In the event of no observed data for imputation, history of pancreatitis will be used as the only 
classification factor for the purpose of identifying non-missing data for imputation. Additional 
factors, such as age and gender may be considered to further classify the imputation categories if 
supported by data.  
The item and composite scores will be imputed separately 
• The Month 6 (primary analysis time point) score will be calculated from the non-missing 
weekly scores from Weeks 23 to 27 and the Month 12 score will be calculated from the 
non-missing weekly scores from Weeks 49 to 53. If all weekly scores during the period 
are missing, the missing score at the primary analysis time point will be imputed using the 
data from the week that is the closest to Day 169 and within a ± 30 days window, the 
missing Month 12 data will be imputed using the data from the week that is the closest to 
the Day 351 and within a ± 30 days window. If 2 or more visits with equal distance, then 
the average or worst will be used. The item and composite scores will be imputed 
separately. 
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ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
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The tables below list the summaries and analyses to be performed for the FCS symptom item 
and composite scores 
Observed Data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
Average FCS 
Symptom – item 
score and 
composite score 
Baseline is defined as the 
average during the 
screening period and up to 
Day 1. If all assessments 
during the period are 
missing, the baseline will 
be considered as missing 
Weekly average. If a 
patient has less than 
4 assessments in a week, 
the weekly score will be 
considered as missing 
1. Descriptive statistics of score, change 
and percent change over time in the 
FAS 
2. Frequency of patients by abdominal 
pain category (no pain, mild, 
moderate and severe) over time in the 
FAS 
 
 
Month 6 (Primary 
analysis time point) -
average of Weeks 23 to 
27 
Month 12 -average of 
Weeks 49 to 53 
1. Descriptive statistics of score, 
change and percent change at 
Month 6 and Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as 
factors, and the corresponding 
baseline score as a covariate in the 
FAS 
3. Descriptive statistics of abdominal 
pain score, change and percent 
change at Month 6 and Month 12 in 
the subset of FAS patients who 
reported any abdominal pain (pain 
score > 0) at Baseline 
4. ANCOVA model of change from 
baseline in abdominal pain score 
with the two stratification factors and 
treatment group as factors and the 
baseline score as a covariate in the 
subset of FAS patients who reported 
any abdominal pain (pain score > 0) 
at Baseline  
 
Baseline is defined as the 
single observation 
collected at the first day of 
screening with a two-week 
recall 
Weekly average. If a 
patient has less than 
4 assessments within a 
week, the weekly score 
will be considered as 
missing 
Descriptive statistics of score, change and 
percent change over time in the FAS 
 
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Statistical Analysis Plan 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
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Observed Data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
Average FCS 
Symptom – item 
score and 
composite score 
(Continued 
Baseline is defined as the 
single observation 
collected at the first day of 
screening with a two-week 
recall (Continued) 
Month 6 (Primary 
analysis time point) -
average of Weeks 23 to 
27 
Month 12 -average of 
Weeks 49 to 53 
1. Descriptive statistics of score, change 
and percent change at Month 6 and 
Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as factors 
and the corresponding baseline score 
as a covariate in the FAS 
Worst FCS 
Symptom – item 
score and 
composite score 
Baseline is defined as the 
worst during the screening 
period and up to Day 1. If 
all assessments during the 
period are missing, the 
baseline will be considered 
as missing 
Weekly worst. If a patient 
has less than 4 
assessments in a week, the 
weekly score will be 
considered as missing 
1. Descriptive statistics of score, change 
and percent change over time in the 
FAS 
2. Frequency of patients by abdominal 
pain category (no pain, mild, 
moderate and severe) over time in 
the FAS 
 
 
Month 6 (Primary 
analysis time point) - 
worst of Weeks 23 to 27 
Month 12 -worst of 
Weeks 49 to 53 
1. Descriptive statistics of score, change 
and percent change at Month 6 and 
Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as factors 
and the corresponding baseline score 
as a covariate on FAS 
3. Descriptive statistics of abdominal 
pain score, change and percent 
change at Month 6 and Month 12 in 
the subset of ITT patients who 
reported any abdominal pain (pain 
score > 0) at Baseline 
4. ANCOVA model of change from 
baseline in abdominal pain score 
with the two stratification factors and 
treatment group as factors and the 
baseline score as a covariate in the 
subset of ITT patients who reported 
any abdominal pain (pain score > 0) 
at Baseline  
 
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Project Document Effective Date: 15 Aug 2023 
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Observed Data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
Worst FCS 
Symptom – each 
item score and 
composite score 
(Continued 
Baseline is defined as the 
single observation 
collected at the first day of 
screening with a two-week 
recall 
Weekly worst. If a patient 
has less than 4 
assessments in a week, the 
weekly score will be 
considered as missing 
Descriptive statistics of score, change and 
percent change over time in the FAS 
 
 
Month 6 (Primary 
analysis time po–nt) - 
worst of Weeks 23 to 27 
Month 12 -worst of 
Weeks 49 to 53 
1. Descriptive statistics of score, change 
and percent change at Month 6 and 
Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as factors 
and the corresponding baseline score 
as a covariate in the FAS 
 
Imputed Data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
Average FCS 
Symptom – item 
score and 
composite score 
Baseline is defined as the 
average during the 
screening period and up to 
Day 1. If all assessments 
during the period are 
missing, the baseline will 
be considered as missing.  
Missing baseline will be 
imputed using the average 
of non-missing data from 
other patients in the same 
stratification category 
Month 6 (Primary 
analysis time point) -
average of Weeks 23 to 
27 
Month 12 -average of 
Weeks 49 to 53. 
If all weekly scores during 
the period are missing, the 
missing Month 6 score 
will be imputed using the 
data from the week that is 
the closest to Day 169 and 
within a ± 30 days 
window, the missing 
Month 12 data will be 
imputed using the data 
from the week that is the 
closest to the Day 351 and 
within a ± 30 days 
window. If 2 or more 
visits with equal distance, 
then the average will be 
used. 
1. 
Descriptive statistics of score, change 
and percent change at Month 6 and 
Month 12 in the FAS 
2. 
ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as factors 
and the corresponding baseline score 
as a covariate in the FAS  
 
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Statistical Analysis Plan 
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CONFIDENTIAL 
Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
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Imputed Data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
Average FCS 
Symptom – item 
score and 
composite score 
(Continued) 
Baseline is defined as the 
single observation 
collected at the first day of 
screening with a two-week 
recall 
Missing baseline will be 
imputed using the average 
of non-missing data from 
other patients in the same 
stratification category 
Month 6 (Primary 
analysis time point) -
average of Weeks 23 to 
27 
Month 12 -average of 
Weeks 49 to 53. 
If all weekly scores during 
the period are missing, the 
missing Month 6 score 
will be imputed using the 
data from the week that is 
the closest to Day 169 and 
within a ±30 days 
window, the missing 
Month 12 data will be 
imputed using the data 
from the week that is the 
closest to the Day 351 and 
within a ±30 days 
window. If 2 or more 
visits with equal distance, 
then the average will be 
used. 
1. Descriptive statistics of score, 
change and percent change at 
Month 6 and Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as 
factors and the corresponding 
baseline score as a covariate in the 
FAS 
Worst FCS 
Symptom – each 
item score and 
composite score 
Baseline is defined as the 
worst during the screening 
period and up to Day 1. 
If all assessments during 
the period are missing, the 
baseline will be considered 
as missing 
Missing baseline will be 
imputed using the average 
of non-missing data from 
other patients in the same 
stratification category 
Month 6 (Primary 
analysis time point) - 
worst of Weeks 23 to 27 
Month 12 -worst of 
Weeks 49 to 53 
If all weekly scores during 
the period are missing, the 
missing Month 6 score 
will be imputed using the 
data from the week that is 
the closest to Day 169 and 
within a ± 30 days 
window, the missing 
Month 12 data will be 
imputed using the data 
from the week that is the 
closest to the Day 351 and 
within a ± 30 days 
window. If 2 or more 
visits with equal distance, 
then the worst will be 
used. 
1. Descriptive statistics of score, 
change and percent change at Month 
6 and Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as 
factors and the corresponding 
baseline score as a covariate in the 
FAS 
 
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TP-GDO-WW-016-08 
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Project Document Effective Date: 15 Aug 2023 
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4.11.3.4. FCS impacts 
The FCS Impacts Questionnaire includes 13 items addressing potential impacts of FCS on patient 
functioning. These 13 items ask patients to rate the frequency of each impact in the past 7 days during 
the screening period and at each study visit using the following scale: Never = 0, Rarely = 1, 
Sometimes = 2, Often = 3, and Always = 4. Higher scores denote more severe impacts.  
An impacts composite score will be calculated as the average of the non-missing scores across the 
13 impact individual items. If more than 50% of the questions are missing, the impacts composite 
score will be considered as missing for the visit.  
Item-level scores, impacts composite score and their changes from baseline will be summarized by 
treatment group over time using descriptive statistics. 
The change from baseline in the impacts composite scores at the primary analysis time point (average 
of Weeks 23, 25 27) and at Month 12 (average of Weeks 49, 51 and 53) will be analyzed using an 
ANCOVA model with the two randomization stratification factors and treatment group as factors and 
baseline score as a covariate, and will be conducted in the FAS. 
In addition to the analyses described above based on the observed data, the missing values will be 
imputed. The change from baseline in the impacts composite scores at the primary analysis time point 
and at Month 12 based on the imputed data will be analyzed using an ANCOVA model with the two 
randomization stratification factors and treatment group as factors and baseline score as a covariate, 
and will be conducted in the FAS. 
The missing values will be imputed as follows: 
• 
For patients with a missing baseline value, their baseline score will be imputed using the 
average of non-missing data from other patients in the same stratification category. In the 
event of no observed data for imputation, history of pancreatitis will be used as the only 
classification factor for the purpose of identifying non-missing data for imputation. Additional 
factors, such as age and gender may be considered to further classify the imputation categories 
if supported by data.  
• The Month 6 (primary analysis time point) score will be calculated from the non-missing 
scores from Weeks 23, 25 and 27 and the Month 12 score will be calculated from the 
non-missing scores from Weeks 49, 51 and 53. If all weekly scores during the period are 
missing, the missing Month 6 score will be imputed using the data from the week that is the 
closest to Day 169 and within a ± 30 days window, the missing Month 12 data will be imputed 
using the data from the week that is the closest to the Day 351 and within a ± 30 days window. 
If 2 or more visits with equal distance, then the average will be used.  
678354-CS03   Statistical Analysis Plan     | 1.0


Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 66 of 72 
The tables below list the summaries and analyses to be performed for the FCS impact score 
Observed data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
FCS Impacts – 
item score and 
composite score 
Baseline is defined as the 
last non-missing 
assessment on or prior to 
the Day 1 
If data is not available in a 
visit, the score will be 
considered as missing 
Descriptive statistics of score, change and 
percent change over time in the FAS 
 
 
Month 6 (Primary 
analysis time point) - 
average of Weeks 23, 25, 
27 
Month 12 -average of 
Weeks 49, 51 and 53 
1. Descriptive statistics of the impacts 
composite score, change and percent 
change at Month 6 and Month 12 in 
the FAS 
2. ANCOVA model of change from 
baseline in the impact composite 
score with the two stratification 
factors and treatment group as 
factors and the baseline score as a 
covariate in the FAS 
 
Imputed data 
Endpoint 
Baseline 
Post baseline 
Analysis 
FCS Impacts –
composite score 
Baseline is defined as the 
last non-missing 
assessment on or prior to 
the Day 1. 
If all pre-dose composite 
scores are missing, the 
baseline composite score 
will be considered as 
missing.  
Missing baseline will be 
imputed using the average 
of non-missing data from 
other patients in the same 
stratification category 
Month 6 (Primary 
analysis time point) – 
average of Weeks 23, 25, 
27 
Month 12 -average of 
Weeks 49, 51 and 53 
If all composite scores 
during the period are 
missing, the missing 
Month 6 score will be 
imputed using the data 
from the visit that is the 
closest to Day 169 and 
within a ±30 days 
window, the missing 
Month 12 data will be 
imputed using the data 
from the week that is the 
closest to the Day 351 
and within a ±30 days 
window. If 2 or more 
visits with equal 
distance, then the 
average will be used. 
1. Descriptive statistics of the impacts 
composite score, change and 
percent change at Month 6 and 
Month 12 in the FAS 
2. ANCOVA model of change from 
baseline in the impact composite 
score with the two stratification 
factors and treatment group as 
factors and the baseline score as a 
covariate in the FAS  
4.11.3.5. PROMIS Patient Reported Outcome Assessments 
• The PROMIS Pain Interference Short Form 8a contains 8 questions to assess 
self-reported consequences of pain on relevant aspects of patients’ life over the past 
seven days. This includes the extent to which pain hinders engagement with social, 
cognitive, emotional, physical, and recreational activities. The pain interference score 
will be calculated by summing the values of the response to each question to get a raw 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 67 of 72 
score, then converting the raw score to a T-score using the PROMIS scoring manual. 
The T‐score rescales the raw score into a standardized T‐score with a mean of 50 and a 
SD of 10. A T-score of 50 is the average of the United States general population. Higher 
interference pain scores indicate a more severe impact of pain on a patient’s life. If more 
than 50% of the questions are missing, the pain interference score will be considered as 
missing for the visit. If less than or equal to 50% of the questions are missing, the 
missing items will be imputed using the average of the non-missing items and rounded 
to the nearest integer. 
The PROMIS 29+2 Profile v2.1 (PROPr) contains seven PROMIS domains (Physical Function, 
Anxiety, Depression, Fatigue, Pain Interference, Sleep Disturbance, and Ability to Participate in 
Social Roles and Activities), an additional pain intensity 0‐10 numeric rating scale (NRS), plus two 
Cognitive Function Abilities items. The PROPr score will be calculated as: 
• summing the values of the response to each question to get a raw total score for each 
domain. If more than 50% of the questions in a domain are missing, the domain score will 
be considered as missing for the visit. If less than or equal to 50% of the questions in a 
domain are missing, the missing items will be imputed using the average of the 
non-missing items in the same domain and rounded to the nearest integer. 
• converting the raw domain scores to T-scores using the PROMIS scoring manual. 
A T-score of 50 is the average of the United States general population. Higher symptom 
scores indicate increased symptom burden and higher function scores indicate better 
functioning.   
• converting the T‐scores to theta values: theta = (T – 50)/10, applying SAS code using theta 
values to calculate a PROPr score. The code is named “MAUT” (Multi‐Attribute Utility 
Theory) and is availablithub.com/janelhanmer/PROPr.  The PROPr scores range 
from 0 (as bad as dead) to 1 (perfect or ideal health). 
• The PROMIS Cognitive Function Short Form 4a contains 4 questions to assess 
patient-perceived cognitive deficits over the past seven days. The cognitive function score 
will be calculated by summing the values of the response to each question to get a raw 
score, then converting the raw score to a T-score using the PROMIS scoring manual. A T-
score of 50 is the average of the United States general population. Higher cognitive 
function scores indicate better cognitive functioning. If more than 50% of the questions 
are missing, the cognitive function score will be considered as missing for the visit. If less 
than or equal to 50% of the questions are missing, the missing items will be imputed using 
the average of the non-missing items and rounded to the nearest integer. 
The pain interference score, PROPr domain and total scores, and cognitive function score will be 
summarized by treatment group over time using descriptive statistics. The changes from baseline at 
the primary analysis time point (average of Weeks 23, 25, 27) and at Month 12 (average of Weeks 51 
and 53 for PROPr domain and total scores and cognitive function scores, average of Weeks 49, 51 and 
53 for pain interference) will be analyzed using an ANCOVA model with the two randomization 
stratification factors and treatment group as factors and the corresponding baseline score as a 
covariate, and will be conducted in the FAS.   
In addition to the analyses described above based on the observed data, the missing values will be 
imputed. The changes from baseline at the primary analysis time point and at Month 12 based on the 
imputed data will be analyzed using an ANCOVA model with the two randomization stratification 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 68 of 72 
factors and treatment group as factors and the corresponding baseline score as a covariate, and will 
be conducted in the FAS. The missing values will be imputed as follows: 
• For patients with a missing baseline value, their baseline score will be imputed using the 
average of non-missing data from other patients in the same stratification category. In the 
event of no observed data for imputation, history of pancreatitis will be used as the only 
classification factor for the purpose of identifying non-missing data for imputation. 
Additional factors, such as age and gender may be considered to further classify the 
imputation categories if supported by data.  
• The Month 6 (primary analysis time point) score will be calculated from the non-missing 
scores from Weeks 23, 25 and 27 , the Month 12 pain interference score will be calculated 
from the non-missing scores from Weeks 49, 51 and 53, and the Month 12 PROPr domain 
and total scores and cognitive function score will be calculated from the non-missing 
scores from Weeks 51 and 53. If all scores during the period are missing, the missing 
Month 6 score will be imputed using the data from the week that is the closest to Day 169 
and within a ± 30 days window, the missing Month 12 pain interference score will be 
imputed using the data from the week that is the closest to the Day 351 and within a 
± 30 days window, the missing Month 12 PROPr domain and total scores and cognitive 
function score will be imputed using the data from the week that is the closest to the 
Day 358 and within a ± 30 days window. If 2 or more visits with equal distance, then the 
average will be used.  
The tables below list the summaries and analyses to be performed for the PROPr domain and 
total scores, pain interference score, and cognitive function score 
Observed data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
PROMIS 29+2 
domain and total 
scores, cognitive 
function scores 
Baseline is defined as the 
last non-missing 
assessment on or prior to 
Day 1 
If data is not available in a 
visit, the score will be 
considered as missing 
Descriptive statistics of domain and total 
scores, change and percent change over 
time in the FAS 
 
 
Month 6 (Primary 
analysis time point) - 
average of Weeks 23, 25, 
27 
Month 12 -average of 
Weeks 51 and 53 
1. Descriptive statistics of the domain 
and total scores, change and percent 
change at Month 6 and Month 12 in 
the FAS 
2. ANCOVA model of change from 
baseline in the domain and total scores 
with the two stratification factors and 
treatment group as factors and the 
corresponding baseline score as a 
covariate in the FAS 
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 69 of 72 
Observed data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
Pain interference  Baseline is defined as the 
last non-missing 
assessment on or prior to 
Day 1 
If data is not available in a 
visit, the score will be 
considered as missing 
Descriptive statistics of score, change and 
percent change over time in the FAS 
 
 
Month 6 (Primary 
analysis time point) - 
average of Weeks 23, 25, 
27 
Month 12 -average of 
Weeks 49, 51 and 53 
1. Descriptive statistics of the scores, 
change and percent change at Month 6 
and Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as factors 
and the corresponding baseline score 
as a covariate in the FAS 
 
Imputed data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
PROMIS 29+2 
domain and total 
scores, cognitive 
function scores 
Baseline is defined as the 
last non-missing 
assessment on or prior to 
Day 1. If all pre-dose 
scores are missing, the 
baseline score will be 
considered as missing.  
Missing baseline will be 
imputed using the average 
of non-missing data from 
other patients in the same 
stratification category 
Month 6 (Primary 
analysis time point) - 
average of Weeks 23, 25, 
27 
Month 12 -average of 
Weeks 51 and 53 
If all scores during the 
period are missing, the 
missing Month 6 score 
will be imputed using the 
data from the visit that is 
the closest to Day 169 and 
within a ± 30 days 
window, the missing 
Month 12 data will be 
imputed using the data 
from the week that is the 
closest to the Day 358 and 
within a ± 30 days 
window. If 2 or more visit 
with equal distance, then 
the average will be used. 
1. Descriptive statistics of the domain 
and total scores, change and percent 
change at Month 6 and Month 12 in 
the FAS 
2. ANCOVA model of change from 
baseline in the domain and total 
scores with the two stratification 
factors and treatment group as 
factors and the corresponding 
baseline score as a covariate in the 
FAS 
  
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Parexel International 
 
ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
Page 70 of 72 
Imputed data 
Endpoint 
Baseline 
Post-baseline 
Analysis 
Pain interference  Baseline is defined as the 
last non-missing 
assessment on or prior to 
Day 1. If all pre-dose 
composite scores are 
missing, the baseline 
composite score will be 
considered as missing.  
Missing baseline will be 
imputed using the average 
of non-missing data from 
other patients in the same 
stratification category 
Month 6 (Primary 
analysis time point) - 
average of Weeks 23, 25, 
27 
Month 12 -average of 
Weeks 49, 51 and 53 
If all composite scores 
during the period are 
missing, the missing 
Month 6 score will be 
imputed using the data 
from the visit that is the 
closest to Day 169 and 
within a ± 30 days 
window, the missing 
Month 12 data will be 
imputed using the data 
from the week that is the 
closest to the Day 351 and 
within a ± 30 days 
window. If 2 or more 
visits with equal distance, 
then the average will be 
used. 
1. Descriptive statistics of the score, 
change and percent change at 
Month 6 and Month 12 in the FAS 
2. ANCOVA model of change from 
baseline with the two stratification 
factors and treatment group as 
factors and the corresponding 
baseline score as a covariate in the 
FAS 
 
4.11.3.6.  The Patient Global Impression of Severity Scale (PGIS) score and Patient Global 
Impression of Change (PGIC) Score 
The PGIS score (scaled None = 0, Mild = 1, Moderate = 2, Severe = 3, and Very severe=4), change 
from baseline in PGIS,  and PGIC score (scaled Much better = 1, A little better= 2, No change = 3, 
A little worse = 4, and Much worse =5) will be tabulated by severity or change category and by 
treatment group over time.  
Change from baseline in PGIS at the primary time point (average at Weeks 23, 25, 27) and at 
Month 12 (average of Weeks 51 and 53) will be classified to 2 categories: improved (defined as 
change from baseline < 0) and not improved (defined as change from baseline ≥ 0). The data will be 
analyzed using a logistic regression model with the two randomization stratification factors and 
treatment group as factors and baseline PGIS score as a covariate, and will be conducted in the FAS. 
PGIC score at the primary time point (average at Weeks 23, 25, 27) and at Month 12 (average of 
Weeks 51 and 53) will be classified to 2 categories: improved (defined as PGIC score = Much better 
[< 1.5] or A little better [1.5 to < 2.5]) and not improved (PGIC score = No change [2.5 to < 3.5], 
A little worse [3.5 to < 4.5], Much worse [≥ 4.5]) and analyzed using a logistic regression model with 
the two randomization stratification factors and treatment group as factors and baseline PGIS score 
as a covariate, and will be conducted in the FAS.  
4.11.3.7. Diet Questions 
Responses to daily dietary questions will be listed.   
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ISIS 678354-CS3 
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TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
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Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
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4.11.3.8. Number of ER Visits, Incidence of All-cause Hospitalization, and Number of 
In-patient Days 
The yearly rate of ER visits, all-cause hospitalization, and in-patient days during the treatment period 
will be summarized using descriptive statistics. The yearly rates for each patient will be calculated as 
number of ER visits, incidence of all-cause hospitalization, or number of in-patient days times 
365.25 divided by number of days during the treatment period.  
If supported by data, the number of ER visits and incidence of all-cause hospitalization during the 
treatment period may be compared between pooled ISIS 678354 treatment group and placebo group 
using a Negative Binomial regression model in the FAS. The model will include the treatment group 
and the 2 stratification factors as the factors. The logarithm of time in year that each patient observed 
during the Treatment Period will be used as an offset variable.  
The yearly rate of in-patient days may be compared between pooled ISIS 678354 treatment group 
and placebo group using an ANCOVA model with the treatment group and the 2 stratification factors 
as the factors, and will be conducted in the FAS.    
4.12. 
Determination of Sample Size 
Based upon prior clinical trial experience with FCS patients, the SD of the percent change from 
Baseline in TGs is approximately 46%. With 14 patients in each ISIS 678354 treatment group and 
14 in the pooled placebo group, there would be a 90% power to detect a 60% difference between each 
ISIS 678354 treatment group and pooled placebo group at an alpha level of 0.05 (two-sided), 
assuming 60% reduction in the ISIS 678354 treatment patients and no change in the placebo patients. 
Approximately 60 patients will be enrolled in this trial to account for potential early dropouts and to 
facilitate general safety evaluation. 
Eligible patients will be randomized 1:1 to Cohort A or Cohort B and each cohort further randomized 
2:1 (ISIS 678354:placebo) and stratified for: 
• Prior history of pancreatitis within 10 years prior to Screening* vs. no history of 
pancreatitis or no history within 10 years prior to Screening 
• Previous treatment with volanesorsen 
* History of pancreatitis is defined as a recorded diagnosis of acute pancreatitis or hospitalization for 
severe abdominal pain consistent with acute pancreatitis and for which no alternate diagnosis was 
made 
4.13. 
Changes in the Conduct of the Study or Planned Analysis 
There are no changes from the planned analysis methodology described in the protocol. 
 
 
 
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ISIS 678354-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-08 
CONFIDENTIAL 
Project Document Version No. 4.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: 15 Aug 2023 
Related to:  SOP-GDO-WW-019 
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5. 
REFERENCES 
Banks, P. A., Bollen, T. L., Dervenis, C., … Vege, S. S. (2013). Classification of acute pancreatitis-
-2012: revision of the Atlanta classification and definitions by international consensus. Gut, 62(1), 
102–11. 
Carpenter, J. R., Roger, J. H., & Kenward, M. G. (2013). Analysis of Longitudinal Trials with 
Protocol Deviation: A Framework for Relevant, Accessible Assumptions, and Inference via 
Multiple Imputation. Journal of Biopharmaceutical Statistics, 23(6), 1352–1371. 
Imbens, G. W., & Kolesár, M. (2016). Robust Standard Errors in Small Samples: Some Practical 
Advice. Review of Economics and Statistics, 98(4), 701–712. 
Little, R., & Rubin, D. (2002). Statistical analysis with missing data. Second Edition, s 2002. New 
York: John Wiley & Sons. 
Schafer. (1997). Analysis of Incomplete Multivariate Data, New York: Chapman and Hall/CRC. 
doi:10.1201/9781439821862 
Schafer, J. L. (1999). Multiple imputation: a primer. Stat Methods Med Res, 8, 3–15. 
Shankar, G., Arkin, S., Cocea, L., … Yim, S. (2014). Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical 
recommendations. Aaps j, 16, 658–73. 
Wang, Y.-M. C., Wang, J., Hon, Y. Y., Zhou, L., Fang, L., & Ahn, H. Y. (2016). Evaluating and 
Reporting the Immunogenicity Impacts for Biological Products—a Clinical Pharmacology 
Perspective. The AAPS Journal, 18(2), 395–403. 
  
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