Conditions: Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Keywords: Polyneuropathy Amyloidosis ATTR TTR
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 168
Healthy volunteers: no

Brief summary:
The main objective of this study was to evaluate the efficacy of eplontersen as compared with the historical control of the placebo cohort in the NEURO-TTR trial (NCT01737398/2012-001831-30), in subjects with hereditary transthyretin-mediated amyloidosis polyneuropathy (hATTR-PN). For more information, please visit http://www.neuro-ttransform.com/.

Detailed description:
This study was a multicenter, open-label study in up to 168 participants, who were randomized to receive subcutaneous (SC) injections of either eplontersen once every 4 weeks or inotersen once a week. Participants also received daily supplemental doses of the recommended daily allowance of vitamin A. Participants included in the inotersen reference arm crossed over to eplontersen at Week 37 after completing the Week 35 assessments.

Arms:
arm 1: Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81. arm 2: Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.

Interventions: intervention 1: Inotersen intervention 2: Eplontersen
Intervention descriptions: intervention 1: Inotersen by subcutaneous injection intervention 2: Eplontersen by subcutaneous injection

Protocol document:
Prot_SAP_000.pdf: 
 
 
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of ION-
682884 in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy 
 
NCT04136184 
 
03 Jun 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ionis.com 


                    ION-682884-CS3                                                                                                                  Ionis Pharmaceuticals, Inc. 
Page 1 of 7 
 
Summary of Clinical Study Results 
NEURO-TTRansform: A Study to Evaluate the Efficacy and 
Safety of Eplontersen (Formerly Known as ION-682884, IONIS-
TTR-LRx and AKCEA-TTR-LRx) in Participants With Hereditary 
Transthyretin-Mediated Amyloid Polyneuropathy 
 
Protocol #: ION-682884-CS3 
Study dates: December 2019 to July 2023  
Thank you to the participants who took part in the study, “A Study to Evaluate the 
Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx 
and AKCEA-TTR-LRx)”, also known as the NEURO-TTRansform study. 
 
Why was this study done? 
Hereditary transthyretin (hATTR) amyloidosis is an uncommon and not well-known 
disease that gets worse quickly, cannot be reversed and if not treated can be deadly. 
hATTR is caused by changes in a specific gene that makes a protein called 
transthyretin (TTR). Genes are pieces of DNA that provide instructions to make a 
specific type of genetic material called messenger ribonucleic acid (mRNA), which is 
like a recipe for making proteins in the body. Genetic diseases are passed on from 
parents to children through altered (mutated) genes. In hATTR, these mutated genes 
can lead to unstable TTR proteins that break apart into smaller parts and can form 
clumps called amyloid fibrils. These clumps build up in various tissues in the body.  
When the build-up happens in nerves (units like wires that send messages between 
the brain and the body), the nerves become damaged. Damaged nerves can cause 
problems with movement, loss of feeling (numbness) in the arms and legs 
(sensorimotor neuropathy) and affect bodily functions like digestion (the process your 
body uses to break down the food you eat into smaller parts) and urination (how your 
body removes liquid waste; peeing). People have different presentations of hATTR. 
The type of hATTR presentation that affects the nerves, digestion, and urination is 
called hATTR with polyneuropathy (hATTR-PN). Between 10,000 and 50,000 people 
worldwide are suffering from hATTR-PN. After being diagnosed with hATTR-PN, 
people who are untreated usually live for about 5 to 15 more years. 
 
In this study, researchers looked at a potential new medicine called eplontersen. 
Eplontersen is an antisense oligonucleotide (ASO), a type of medicine that attaches 
itself to hATTR mRNA. When eplontersen attaches to the mRNA for TTR protein, it 
causes the mRNA to break down. Breaking down mRNA means that less of the 
unstable protein is made. As a result, the cells (the smallest units of any living thing; 
the building blocks of life) in the body make less of the damaging TTR protein, which 


                    ION-682884-CS3                                                                                                                  Ionis Pharmaceuticals, Inc. 
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can be helpful for people with hATTR-PN to better manage their disease. 
Eplontersen combines the ASO part of the medicine with a substance called 
triantennary N-acetyl galactosamine (GalNAc) to make a combined ASO-GalNAc 
medicine. This ASO-GalNAc combination helps the ASO medicine get taken up 
better by the liver, which is where the TTR protein is made before it is circulated 
throughout the body. Targeting the GalNAc-ASO to liver cells brings the medicine to 
those cells in the body where TTR protein is created and where it is most needed. 
 
This study helped researchers find out if the medicine called eplontersen lowered the 
TTR protein, was safe and improved the quality of life for people with hereditary 
transthyretin-mediated amyloid polyneuropathy (hATTR-PN). 
 
When was this study done? 
This study started in December 2019 and ended in July 2023. 
 
Who took part in this study? 
People could take part in the study if they fit the following criteria: 
• Were at least 18 years old, but not older than 82 years  
• Used highly effective contraception (birth control) methods or were abstinent 
(not have sex) during the course of the study 
• Had been diagnosed with hATTR-PN 
• Willing to take vitamin A supplements 
People could not take part in the study if they fit the following criteria: 
• Had any important issues found in medical history, laboratory tests, or physical 
examinations that could make them unsuitable to take part in the study  
• Had been diagnosed with other types of amyloidosis (amyloidosis has other 
causes, for example mutations in genes other than hATTR) 
• 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? 
Overall, 168 people took part in this study (participants), of whom 116 (69%) were men 
and 52 (31%) were women.  
The study took place at 40 clinics in Argentina, Australia, Brazil, Canada, Cyprus, 
France, Germany, Italy, New Zealand, Portugal, Spain, Sweden, Taiwan, Turkey, and 
the United States.  


                    ION-682884-CS3                                                                                                                  Ionis Pharmaceuticals, Inc. 
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• 26 participants (15%) enrolled in North America 
• 64 participants (38%) enrolled in Europe 
• 78 participants (46%) enrolled in South America, Australasia/Asia  
What happened during the study? 
What did researchers want to know? 
The main goal of the NEURO-TTRansform study was to see how well eplontersen 
worked in adult participants with hATTR-PN compared with participants who received 
placebo in a previous study called NEURO-TTR, which compared inotersen 
treatment against placebo in participants with ATTRv-PN. Inotersen is a different 
ASO medicine similar to eplontersen, but is not the same, and is not targeted to liver 
cells. In addition, a small group of participants were treated with inotersen until Week 
35 of the study and then switched to receiving eplontersen. A placebo is an inactive 
substance that looks like and is administered as the study medicine but does not 
actually contain any medicine. 
The main questions researchers wanted to answer in this study were the following: 
• Does eplontersen change the levels of TTR in the blood? 
• Does eplontersen help improve the symptoms of nerve damage in adults 
with hATTR-PN? 
To address these questions, participants were given injections of eplontersen under 
the skin every 4 weeks until the final dose at week 81. Participants could receive their 
treatment at the study center or do it at home by themselves or with the help of a 
caregiver or home healthcare provider. Regardless of the treatment they received, all 
participants were required to take vitamin A supplements every day. 
What treatments were studied? 
• Eplontersen, 45 milligrams (mg), given every 4 weeks as an injection under 
the skin (subcutaneous) from Day 1 to Week 81. 
• Inotersen, 300 milligrams (mg), given every week as an injection under the 
skin (subcutaneous) from weeks 1-34 and then eplontersen, 45 mg, from 
Week 37 to 81. 
How was the study done? 
There are many types of clinical studies. This study can be described as follows: 
• Phase 3: This phase is usually the last phase of clinical research before a new 
medicine is submitted to government authorities for marketing approval. A 
study at this phase is used to confirm the effect of a medicine (how well it 
works) and learn more about the medicine’s safety (side effects from the 
medicine) and tolerability (side effects from medicine after repeated use). 
• Randomized: Who got eplontersen versus inotersen was decided randomly by 
a computer program. 


                    ION-682884-CS3                                                                                                                  Ionis Pharmaceuticals, Inc. 
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• Open label: A type of research study where both the researchers and the 
participants know which treatment is being given. 
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 period, participants provided their written consent 
(agreement) to how the study would be done (the study procedures) and 
underwent a review process to determine whether they were eligible to 
participate in the study, including completing a physical exam, answering 
questions about their medical and disease history, and providing blood and 
urine for samples for laboratory testing. 
• The screening period lasted up to 10 weeks. 
Treatment Period 
• Following the screening period, participants were randomly assigned (meaning 
assigned by chance by a computer program) to receive either eplontersen or 
inotersen in a ratio of 6 participants to receive eplontersen for every 1 person 
to receive inotersen. This arrangement ensured a balanced assignment of 
participants to each group. 
• Participants in the eplontersen group received 45 mg of eplontersen injected 
under the skin once every 4 weeks for up to 81 weeks.  
• Participants in the inotersen group first received 300 mg of inotersen injected 
under the skin once a week for up to 34 weeks, then switched to receiving 
45 mg of eplontersen injected under the skin once every 4 weeks from week 
37 to week 81.  
• Throughout the study, all participants were given daily vitamin A supplements. 
• The treatment period lasted for 84 weeks (a little over 1 and a half years).  
Follow-up Period 
• After ending their treatment, participants who were eligible had the option to 
join a long-term extension study (ION-682884-CS13) where they would 
continue to receive eplontersen every 4 weeks. 
• The long-term extension study allowed researchers to collect more information 
on the safety and effectiveness of eplontersen.  
• Participants who did not move on to the long-term extension study entered a 
20-week follow-up period after the last dose to monitor for side effects (safety). 
 
Throughout the study, all participants had a minimum of 11 visits to the study site 
starting from Week 1. During these visits, participants had various tests done, 
including checking platelet count, kidney function, urine protein levels, and liver 
function. Some participants also had extra blood samples taken to assess how the 
medicine was being processed by the body. 
 


                    ION-682884-CS3                                                                                                                  Ionis Pharmaceuticals, Inc. 
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What were the results of the study? 
Out of the 144 participants who were in the eplontersen group, 135 (94.4%) reached 
week 66 of the study. Out of the 24 participants in the inotersen group, 20 (83.3%) 
reached week 66.   
The information that was collected (data) showed that eplontersen worked better 
compared to historical placebo for lowering the amount of TTR protein in the blood. 
The reduction in TTR protein was about 82% for the eplontersen group and about 
11% in the historical placebo group from the NEURO-TTR study. The data also 
showed that nerve damage in participants who received eplontersen was halted and 
participants had improved wellbeing (quality of life) when compared with the historical 
placebo group. Nerve damage was measured by the modified neuropathy impairment 
score plus seven (mNIS+7) test and quality of life (QOL) was measured by 
participants completing the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) 
questionnaire. The Norfolk QoL-DN includes questions for the person to answer 
about various aspects of their daily life, such as how well they could perform basic 
daily activities, the state of their emotional well-being, and their experiences with 
social activities. 
The positive effects seen in participants treated with eplontersen continued through 
the end of the study. 
 
What medicine-related side effects did participants have during the 
study? 
A summary of the medicine-related side effects that happened during the study is 
shown below. Not all participants had side effects. Side effects are undesirable 
experiences associated with the use of a medicine.  
A side effect is called serious when it results in death, is life-threatening, causes lasting 
problems, or requires hospital care. 
• Total amount of participants that participated in the study: 168   
• 140 out of 144 participants (97%) in the eplontersen group compared with 60 
out of 60 participants (100%) in the historical placebo group had treatment 
emergent side effects. 
• 21 out of 144 participants (15%) in the eplontersen group compared with 12 out 
of 60 participants (20%) in the historical placebo group had serious treatment 
emergent side effects. 
• 8 out of 144 participants (5%) in the eplontersen group compared with 2 out of 
60 participants (3%) stopped treatment with study drug due to side effects. 
• 3 participants in the eplontersen group died during the study.  Their doctors 
considered their deaths to not be due to eplontersen. 
 


                    ION-682884-CS3                                                                                                                  Ionis Pharmaceuticals, Inc. 
Page 6 of 7 
 
The most common side effects that were reported in at least 10% of participants 
treated with eplontersen were the following: 
Commonly Reported Side Effects 
Side Effect Reported 
Eplontersen Group 
(144 participants) 
Historical Placebo Group 
(60 participants) 
Urinary tract infection 
28 out of 144 participants  
(19%) 
11 out of 60 participants 
(18%) 
COVID-19 
48 out of 144 participants  
(33%) 
0a 
Diarrhoea  
28 out of 144 participants  
(19%) 
12 out of 60 participants  
(20%) 
Nausea 
16 out of 144 participants  
(11%) 
7 out of 60 participants  
(12%) 
Vitamin A deficiency 
17 out of 144 participants  
(12%) 
0b 
a = before the COVID-19 pandemic 
b = no side effects were reported because Vitamin A test results were blinded in the NEURO-TTR study. Blinding means 
keeping certain information secret from either the participants, the researchers, or both- like a blindfold in a game, where you 
cannot see what is happening. Blinding helps make sure that the results of the study are as fair and accurate as possible. 
For more information on the study results, refer to the websites listed at the end of this 
summary. 
 
How has this study helped participants and researchers? 
Overall, researchers learned that participants who received treatment with eplontersen 
showed improvements in their condition. Specifically, participants had significantly 
lower levels of the TTR protein in their blood, their symptoms of hATTR-PN did not 
progress, and they reported improved quality of life compared with those who had 
received a placebo in a previous study. 
Findings from this study may be used in other studies to learn more about the use of 
eplontersen in people with hATTR. 
 
Are there plans for further studies? 
Further clinical studies with eplontersen are ongoing at this time that can be helpful for 
other conditions.  
 
Where can I find out more about this study? 
• Official Title of this Study: A Phase 3 Global, Open-Label, Randomized Study 
to Evaluate the Efficacy and Safety of ION-682884 in Patients With Hereditary 
Transthyretin-Mediated Amyloid Polyneuropathy   


                    ION-682884-CS3                                                                                                                  Ionis Pharmaceuticals, Inc. 
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• Protocol Number: ION-682884-CS3 
• EU Study Number: 2019-001698-10 
Clinical Trials register - Search for 2019-001698-10 
• US Study Number: NCT04136184 
https://clinicaltrials.gov/study/NCT04136184 
• Journal of the American Medical Association (JAMA) Publication 
Coelho T, Marques W Jr, Dasgupta NR, et al. Eplontersen for Hereditary 
Transthyretin Amyloidosis With Polyneuropathy. JAMA. 2023;330(15):1448-1458. 
doi:10.1001/jama.2023.18688 


 
 
 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
 
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the 
Efficacy and Safety of ION-682884 in Patients with Hereditary 
Transthyretin-Mediated Amyloid Polyneuropathy 
 
Amendment 5 – 12 August 2021 
 
EudraCT No:  2019-001698-10  
NEURO - TTRANSFORM  
Strategy to Improve Patient Outcomes by Silencing TTR Formation in hATTR-PN 
 
Trial Sponsor 
Ionis Pharmaceuticals 
2855 Gazelle Court 
Carlsbad, CA 92010 
Telephone Number:  +01 760 931 9200 
Fax Number:  +01 760 603 2700 
Key Sponsor Contact 
Date 
12 August 2021 
 
 
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ION-682884-CS3 
CONFIDENTIAL 
Amendment 5
Protocol 
12 August 2021
 
2 
ION-682884-CS3 
Amendment 5 
EudraCT No:  2019-001698-10 
 
Clinical Phase:  3 
 
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the 
Efficacy and Safety of ION-682884 in Patients with Hereditary 
Transthyretin-Mediated Amyloid Polyneuropathy 
 
Protocol History  
Original Protocol: 
28 June 2019 
Amendment 1: 
6 August 2019 
Amendment 2  
18 September 2019 
Amendment 3  
30 January 2020 
Amendment 4: 
11 December 2020 
 
NEURO – TTRANSFORM 
Strategy to Improve Patient Outcomes by Silencing TTR Formation in hATTR-PN 
 
 
 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA 92010 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. that must not be disclosed to anyone 
other than the recipient study staff and members of the independent ethics committee, institutional review board, or 
authorized regulatory agencies.  This information cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Ionis Pharmaceuticals, Inc.. 
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ION-682884-CS3 
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Protocol 
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3 
Protocol Signature Page 
 
Protocol Number: 
ION-682884-CS3 
Protocol Title: 
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the 
Efficacy and Safety of ION-682884 in Patients with Hereditary 
Transthyretin-Mediated Amyloid Polyneuropathy 
Amendment:  
Amendment 5 
Date:  
 
12 August 2021 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled 
“A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of 
ION-682884 in Patients with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy”, 
dated12 August 2021, 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) 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT .......................................................................................................10 
PROTOCOL SYNOPSIS ..............................................................................................................17 
STUDY SCHEMA.........................................................................................................................26 
SCHEMATIC PATIENT FLOW THROUGH THE STUDY .......................................................27 
STUDY GLOSSARY ....................................................................................................................28 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................31 
1.1. 
Objectives ...................................................................................................................31 
1.1.1. 
Primary Objectives .....................................................................................................31 
1.1.2. 
Secondary Objectives .................................................................................................31 
1.1.3. 
Safety Objectives ........................................................................................................31 
1.1.4. 
Additional/Exploratory Objectives .............................................................................31 
1.1.4.1. 
Efficacy Objectives .....................................................................................................31 
1.1.4.2. 
Pharmacokinetic Objectives .......................................................................................32 
1.2. 
Study Endpoints ..........................................................................................................32 
1.2.1. 
Interim Analysis Co-Primary Efficacy Endpoints at Week 35 ...................................32 
1.2.2. 
Interim Analysis Key Secondary Efficacy Endpoint at Week 35 ...............................32 
1.2.3. 
Final Analysis Co-Primary Efficacy Endpoints .........................................................32 
1.2.4. 
Final Analysis Secondary Endpoints ..........................................................................32 
1.2.5. 
Safety Endpoints .........................................................................................................33 
1.2.6. 
Additional/Exploratory Endpoints ..............................................................................33 
1.2.6.1. 
Efficacy Endpoints ......................................................................................................33 
1.2.6.2. 
Pharmacokinetic Endpoints ........................................................................................34 
2. 
BACKGROUND AND RATIONALE .......................................................................34 
2.1. 
Overview of Disease ...................................................................................................34 
2.1.1. 
Disease Background ...................................................................................................34 
2.1.2. 
Overview of Target – Transthyretin ...........................................................................35 
2.1.3. 
Current Therapies .......................................................................................................35 
2.2. 
Therapeutic Rationale .................................................................................................36 
2.3. 
ION‑682884 ................................................................................................................37 
 
 
 
 
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2.3.3. 
Preclinical Experience ................................................................................................38 
2.3.4. 
Clinical Experience .....................................................................................................38 
 
 
2.5. 
Benefit-Risk Assessment ............................................................................................42 
2.5.1. 
Benefit Assessment .....................................................................................................42 
2.5.2. 
Risk Assessment .........................................................................................................43 
2.5.3. 
Overall Assessment of Benefit:Risk ...........................................................................44 
3. 
EXPERIMENTAL PLAN ..........................................................................................44 
3.1. 
Study Design ...............................................................................................................44 
3.2. 
Number of Study Centers ...........................................................................................45 
3.3. 
Number of Patients .....................................................................................................45 
3.4. 
Overall Study Duration and Follow-up ......................................................................45 
3.4.1. 
Screening and Baseline Assessment ...........................................................................45 
3.4.2. 
Treatment Period ........................................................................................................45 
3.4.3. 
Post-Treatment Evaluation Period and Long-Term Follow up ..................................46 
3.5. 
End-of-Study ...............................................................................................................46 
3.6. 
Data and Safety Monitoring Board .............................................................................46 
4. 
PATIENT ENROLLMENT ........................................................................................46 
4.1. 
Screening ....................................................................................................................46 
4.2. 
Randomization ............................................................................................................47 
4.3. 
Replacement of Patients .............................................................................................47 
5. 
PATIENT ELIGIBILITY ...........................................................................................47 
5.1. 
Inclusion Criteria ........................................................................................................47 
5.2. 
Exclusion Criteria .......................................................................................................48 
6. 
STUDY PROCEDURES ............................................................................................50 
6.1. 
Study Schedule ...........................................................................................................50 
6.1.1. 
Screening and Baseline Assessments .........................................................................50 
6.1.2. 
Day 1/Randomization .................................................................................................51 
6.1.3. 
Treatment Period ........................................................................................................51 
6.1.4. 
End-of-Treatment Assessment Visit ...........................................................................53 
6.1.5. 
Post-Treatment Evaluation Period ..............................................................................53 
6.2. 
Laboratory Assessments .............................................................................................53 
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6.3. 
Restriction on the Lifestyle of Patients .......................................................................53 
6.3.1. 
Contraception Requirements ......................................................................................53 
6.3.2. 
Other Requirements ....................................................................................................54 
7. 
ION-682884 / ISIS 420915 (INOTERSEN) ...............................................................55 
7.1. 
ION-682884 / ISIS 420915 (Inotersen) Description ..................................................55 
7.1.1. 
ION‑682884 ................................................................................................................55 
7.1.2. 
ISIS 420915 (Inotersen) ..............................................................................................55 
7.2. 
Packaging and Labeling ..............................................................................................55 
7.3. 
ION-682884 / ISIS 420915 (Inotersen) Accountability .............................................55 
8. 
TREATMENT OF PATIENTS ..................................................................................55 
8.1. 
ION-682884 / ISIS 420915 (Inotersen) Administration .............................................55 
8.2. 
Other Protocol-Required Drugs ..................................................................................56 
8.3. 
Other Protocol-Required Treatment Procedures ........................................................56 
8.4. 
Treatment Precautions ................................................................................................56 
8.5. 
Safety Monitoring Rules .............................................................................................56 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ..................................................57 
8.5.2. 
Safety Monitoring for Renal Function ........................................................................58 
8.5.3. 
Safety Monitoring Rules for Platelet Count Results...................................................59 
8.5.4. 
Safety Monitoring for Minor Bleeding Events ...........................................................60 
8.5.5. 
Safety Monitoring Rules for Ocular Effects ...............................................................60 
8.6. 
Stopping Rules ............................................................................................................61 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations .........................................................61 
8.6.2. 
Stopping Rules for Renal Function Test Results and Temporary Stopping 
Rules for Renal Function Test Results .......................................................................61 
8.6.3. 
Stopping Rule for Platelet Count Results ...................................................................62 
8.6.4. 
Stopping Rule for Ocular Effects ...............................................................................65 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................65 
8.8. 
Discontinuation of ION-682884 or Inotersen Treatment ...........................................65 
8.9. 
Discontinuation of Study Participation .......................................................................67 
8.10. 
Concomitant Therapy and Procedures ........................................................................67 
8.10.1. 
Concomitant Therapy .................................................................................................67 
8.10.2. 
Concomitant Procedures .............................................................................................68 
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8.11. 
Treatment Compliance ................................................................................................68 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................68 
9.1. 
Sponsor Review of Safety Information ......................................................................68 
9.2. 
Regulatory Requirements ...........................................................................................68 
9.3. 
Definitions ..................................................................................................................69 
9.3.1. 
Adverse Event .............................................................................................................69 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction ............69 
9.3.3. 
Serious Adverse Event (SAE) ....................................................................................70 
9.3.4. 
Adverse Event of Special Interest ...............................................................................70 
9.4. 
Monitoring and Recording Adverse Events ...............................................................71 
9.4.1. 
Serious Adverse Events ..............................................................................................71 
9.4.2. 
Non-Serious Adverse Events ......................................................................................71 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) .........................................71 
9.4.3.1. 
Relationship to the use of ION-682884 or Inotersen ..................................................72 
9.4.3.2. 
Severity .......................................................................................................................72 
9.4.3.3. 
Action Taken with ION-682884 / Inotersen ...............................................................72 
9.4.3.4. 
Treatment Given for Adverse Event ...........................................................................73 
9.4.3.5. 
Outcome of the Adverse Event ...................................................................................73 
9.4.3.6. 
Follow-up of Adverse Event .......................................................................................73 
9.5. 
Procedures for Handling Special Situations ...............................................................74 
9.5.1. 
Abnormalities of Laboratory Tests .............................................................................74 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................74 
9.5.3. 
Dosing Errors ..............................................................................................................74 
9.5.4. 
Contraception and Pregnancy .....................................................................................75 
10. 
STATISTICAL CONSIDERATIONS .......................................................................76 
10.1. 
Study Endpoints ..........................................................................................................76 
10.2. 
Sample Size Considerations .......................................................................................76 
10.3. 
Populations .................................................................................................................76 
10.4. 
Definition of Baseline .................................................................................................77 
10.5. 
Interim Analysis and Multiplicity ...............................................................................78 
10.6. 
Planned Methods of Analysis .....................................................................................79 
10.6.1. 
Demographic and Baseline Characteristics ................................................................80 
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10.6.2. 
Efficacy Analysis ........................................................................................................80 
10.6.2.1. 
Primary Analysis ........................................................................................................80 
10.6.2.2. 
Secondary Analysis ....................................................................................................81 
10.6.2.3. 
Pharmacodynamic Analysis........................................................................................81 
10.6.2.4. 
Exploratory Analyses ..................................................................................................81 
10.6.3. 
Pharmacokinetic and Immunogenicity Analysis ........................................................82 
10.6.3.1. 
Pharmacokinetic Analysis ..........................................................................................82 
10.6.3.2. 
Immunogenicity Analysis ...........................................................................................82 
10.6.4. 
Safety Analysis ...........................................................................................................83 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ...........................................83 
11.1. 
Informed Consent .......................................................................................................83 
11.2. 
Ethical Conduct of the Study ......................................................................................84 
11.3. 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) ..................84 
11.4. 
Patient Confidentiality ................................................................................................84 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................85 
12.1. 
Protocol Amendments ................................................................................................85 
12.2. 
Study Termination ......................................................................................................85 
12.3. 
Study Documentation and Storage .............................................................................85 
12.4. 
Study Monitoring ........................................................................................................86 
12.5. 
Language .....................................................................................................................86 
12.6. 
Compensation for Injury .............................................................................................87 
13. 
REFERENCES ...........................................................................................................88 
14. 
APPENDICES ............................................................................................................91 
APPENDIX A. SCHEDULE OF PROCEDURES .....................................................................92 
APPENDIX B. LIST OF LABORATORY ANALYTES ..........................................................98 
APPENDIX C. PK SAMPLING SCHEDULE .........................................................................100 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES ............................................................102 
 
 
 
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LIST OF TABLES 
Table 1:  
ION-682884 / ISIS 420915 (Inotersen) Characteristics .............................................55 
Table 2:  
ION-682884 / ISIS 420915 (Inotersen) Dosing Information .....................................56 
Table 3: 
Additional Labs to be Performed in the Event of a Platelet Count 
< 100 × 109/L ..............................................................................................................60 
Table 4: 
Actions in Patients with Low Platelet Count ..............................................................64 
 
 
LIST OF FIGURES 
Figure 1: 
Design of ION-682884, a GalNAc-Conjugated Chimeric 2ʹ-MOE 
Phosphorothioate/Phosphate Oligonucleotide (MOE Gapmer) ..................................37 
Figure 2: 
Percent Change from Baseline in TTR over Time (ISIS 420915-CS2 Full 
Analysis Set) ...............................................................................................................39 
Figure 3: 
Change from Baseline in mNIS+7 over Time (ISIS 420915-CS2 Full 
Analysis Set) ...............................................................................................................40 
Figure 4: 
Change from Baseline in Norfolk-QOL-DN over Time (ISIS 420915-CS2 
Full Analysis Set) .......................................................................................................40 
 
 
 
 
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PROTOCOL AMENDMENT 
 
Protocol Number: 
ION-682884-CS3 
Protocol Title: 
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the 
Efficacy and Safety of ION-682884 in Patients with Hereditary 
Transthyretin-Mediated Amyloid Polyneuropathy 
Amendment:  
Amendment 5 
Date:  
 
12 August 2021 
 
This protocol amendment presents updates in comparison with ION-682884-CS3 Protocol 
Amendment , dated 11 December 2020.  
The main purpose of this amendment is to update the frequency of safety monitoring of platelet 
count, eGFR and UPCR, 
 
   
Minor changes (not included in the list of changes below) have also been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design.  The following table 
provides a summary list of major changes to the protocol body.  Protocol Synopsis and the table 
of Schedule of Assessments in Appendix A are updated accordingly.   
Protocol Sections 
Description of Modification 
Rationale 
Synopsis 
Section 5.2  
Exclusion Criteria 
Was: 
9. Previous treatment with Tegsedi™ (inotersen) or 
Onpattro™ (patisiran) or other oligonucleotide or 
RNA therapeutic (including siRNA).   
Is: 
9. Current or previous treatment with Tegsedi™ 
(inotersen) or Onpattro™ (patisiran) or other 
oligonucleotide or RNA therapeutic (including 
siRNA).  This exclusion criterion does not apply 
to COVID-19 mRNA vaccinations. 
Updated to clarify 
that this Exclusion 
Criterion does not 
apply to COVID-19 
mRNA vaccines 
 
 
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Protocol Sections 
Description of Modification 
Rationale 
Section 6.1.3 
Treatment Period 
Was: 
During Study Week 1, patients will report to the Study 
Center for evaluations and ION-682884 or inotersen 
administration on Day 1.  After Week 1, ION-682884 
will be administered once every 4 weeks.  Inotersen 
will be administered once weekly. 
There will be a total of 43 visits [11 mandatory in-
clinic visits and 32 visits that can be completed in-
clinic, at home by a home health-care provider (if 
approved locally), or using a laboratory local to the 
patient upon Investigator approval] during Weeks 1-83 
for study procedures and ION-682884 or inotersen 
administration (see Schedule of Procedures in 
Appendix A).   
Is: 
During Study Week 1, patients will report to the Study 
Center for evaluations and ION-682884 or inotersen 
administration on Day 1.  After Week 1, ION-682884 
will be administered once every 4 weeks through the 
end of the Treatment Period.  Inotersen will be 
administered once weekly up to and including Week 34 
at which time patients will transition to every 4 week 
administration of ION-682884. 
For patients randomized to the ION-682884 treatment 
arm, there will be a total of 43 visits during Weeks 1- 
83 for ION-682884 administration and other study 
procedures (see Schedule of Procedures in 
Appendix A).  Eleven of the 43 visits are mandatory in-
clinic visits, whereas 32 visits can be completed either 
in-clinic, at home by a home health-care provider (if 
approved locally), or by using a local laboratory upon 
Investigator approval. 
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
 
 
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Protocol Sections 
Description of Modification 
Rationale 
Section 6.1.3 
Treatment Period 
For patients randomized to the inotersen reference arm, 
there will be a total of 60 visits during Weeks 1-83 for 
Study Drug administration and other study procedures 
(see Schedule of Procedures in Appendix A).  Eleven 
of the 60 visits are mandatory in-clinic visits, whereas 
49 visits can be completed either in-clinic, at home by 
a home health-care provider (if approved locally), or by 
using a local laboratory upon Investigator approval. 
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
Section 6.1.3 
Treatment Period 
Was: 
During the Treatment Period, frequency of sample 
collection for hematology, chemistry and urinalysis 
will be once every 2 weeks for all patients.  The 
window for blood collections that occur outside clinic 
visits is ± 4 days.  See Section 8.5 for guidance on 
ION-682884 or inotersen dosing relative to hematology 
and chemistry monitoring.  
Is: 
Patients randomized to the ION-682884 treatment arm 
will have their platelet count, eGFR, UPCR, and LFTs 
assessed once every 4 weeks during the Treatment 
Period.   
Patients randomized to the inotersen reference arm will 
have their platelet count, eGFR, UPCR, and LFTs 
assessed every 2 weeks during the Treatment Period up 
to and including Week 34.  After Week 34, patients 
assigned to the inotersen reference arm will transition 
to receive ION-682884 through the end of the 
Treatment Period.  After patients in the inotersen 
reference arm transition to ION-682884, they will 
continue to have every 2-week platelet count, eGFR, 
UPCR, and LFTs measurements for 8 weeks after their 
last dose of inotersen.  They will then be assessed 
every 4 weeks for platelet count, eGFR, UPCR, and 
LFTs through the end of the Treatment Period.   
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
 
 
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Protocol Sections 
Description of Modification 
Rationale 
Section 8.5 Safety 
Monitoring Rules 
Was: 
• The average of all non-missing pre-dose 
assessments.  The window for blood collections 
(hematology and chemistry) that occur outside 
clinic visits is ± 4 days. 
Is: 
• Average of the pre-dose test closest to Day 1 and 
Day 1.  The window for blood collections 
(hematology and chemistry) that occur outside 
clinic visits is ± 4 days. 
Updated to align 
with the Statistical 
Analysis Plan 
Section 8.5.1 Safety 
Monitoring Rules for 
Liver Chemistry 
Tests 
Was: 
The following rules are adapted from the draft 
guidance for industry, “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation,” issued by the U.S. 
Department of Health and Human Services, Food and 
Drug Administration, July 2009.  For a definition of 
Baseline, please refer to guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 
× ULN (or 2 × Baseline value if the Baseline value was 
> ULN) at any time during the study (Treatment or 
Post-Treatment Period), repeat testing should be 
performed within 48 to 72 hours of liver chemistry 
tests (ALT, AST, ALP, total bilirubin and international 
normalized ratio [INR]) to confirm the abnormalities 
and to determine if they are increasing or decreasing.  
There also should be inquiry made about symptoms.  
Additional, confirmatory measurements should also be 
performed if ALT or AST levels increase to 5 × ULN. 
Is: 
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. 
Monitoring frequency will be once every 4 weeks in 
patients randomized to the ION-682884 treatment arm 
until the end of the Treatment Period.   
Patients randomized to the inotersen reference arm will 
have their liver chemistry assessed every 2 weeks 
during the Treatment Period up to and including Week 
34.   
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
 
 
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Protocol Sections 
Description of Modification 
Rationale 
Section 8.5.1 Safety 
Monitoring Rules for 
Liver Chemistry 
Tests (Continued) 
After patients in the inotersen reference arm transition 
to ION-682884 they will continue to have every 
2 week liver chemistry measurements for 8 weeks after 
their last dose of inotersen.  They will then be assessed 
every 4 weeks, through the end of the Treatment 
Period.   
For inotersen patients who terminate treatment before 
the end of the Treatment Period, liver chemistry 
measurements should be monitored once every 2 
weeks, for a duration of 8 weeks.   
In the event of an ALT or AST measurement that is > 3 
× ULN (or 2 × Baseline value if the Baseline value was 
> ULN) at any time during the study (Treatment or 
Post-Treatment Period), repeat testing should be 
performed within 48 to 72 hours of liver chemistry 
tests (ALT, AST, ALP, total bilirubin and international 
normalized ratio [INR]) to confirm the abnormalities 
and to determine if they are increasing or decreasing.  
There also should be inquiry made about symptoms.  
Additional, confirmatory measurements should also be 
performed if ALT or AST levels increase to 5 × ULN. 
 
 
 
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Protocol Sections 
Description of Modification 
Rationale 
Section 8.5.2 Safety 
Monitoring for Renal 
Function 
Was: 
Serum creatinine, estimated glomerular filtration rate 
(eGFRcreat-cys, calculated using the CKD EPI 
creatinine-cystatin C equation [2012]), urinalysis, and 
UPCR should be monitored every 2 weeks in all 
patients taking ION-682884 or inotersen.  In the event 
of a confirmed (as described in Section 8.5) laboratory 
result meeting 1 or more of the following criteria: 
Is: 
Serum creatinine, estimated glomerular filtration rate 
(eGFRcreat-cys, calculated using the CKD-EPI 
creatinine-cystatin C equation [2012]), urinalysis, and 
UPCR should be monitored every 4 weeks in all 
patients randomized to the ION-682884 treatment arm 
and every 2 weeks in all patients randomized to the 
inotersen reference arm, up to and including Week 34.  
After Week 34, patients assigned to the inotersen 
reference arm will transition to receive ION-682884 
through the end of the Treatment Period.  After patients 
in the inotersen reference arm transition to ION-
682884, they will continue to have every 2-week 
measurements for 8 weeks after their last dose of 
inotersen.  They will then be assessed every 4 weeks 
through the end of the Treatment Period..   
For inotersen patients who terminate treatment before 
the end of the Treatment Period, renal function should 
be monitored once every 2 weeks, for a duration of 
8 weeks..  
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
 
 
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Protocol Sections 
Description of Modification 
Rationale 
Section 8.5.3 Safety 
Monitoring Rules for 
Platelet Count 
Results 
Was: 
Platelet monitoring will be every 2 weeks in all patients 
taking ION-682884 and inotersen until the end of the 
Treatment Period.  For patients who terminate 
treatment before the end of the Treatment Period, 
platelets should be monitored once every 2 weeks, for a 
duration of 8 weeks for both treatment arms.  
Is: 
Platelet count monitoring frequency will be once every 
4 weeks in patients randomized to the ION-682884 
treatment arm until the end of the Treatment Period.   
Patients randomized to the inotersen reference arm will 
have their platelet count assessed every 2 weeks during 
the Treatment Period up to and including Week 34.  
After Week 34, patients assigned to the inotersen 
reference arm will transition to receive ION-682884 
through the end of the Treatment Period.  After patients 
in the inotersen reference arm transition to ION-
682884, they will continue to have every 2-week 
platelet count measurements for 8 weeks after their last 
dose of inotersen.  They will then be assessed every 
4 weeks for platelet count through the end of the 
Treatment Period.   
For inotersen patients who terminate treatment before 
the end of the Treatment Period, platelets should be 
monitored once every 2 weeks, for a duration of 
8 weeks.  
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
Table 4:  Actions in 
Patients with Low 
Platelet Count 
Table updated to differentiate between the action to be 
taken for patients receiving ION-682884 verses 
patients receiving inotersen 
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
Appendix A  
Schedule of 
Procedures 
Updated the frequency of safety monitoring to every 
4 weeks for patients receiving ION-682884. 
Updated to reflect 
the different safety 
monitoring 
frequency for 
patients receiving 
ION-682884 and 
inotersen 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy 
and Safety of ION-682884 in Patients with Hereditary Transthyretin-Mediated 
Amyloid Polyneuropathy 
Study Phase 
3 
Indication 
Hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN) 
Primary Objective 
To evaluate the efficacy of ION-682884, based on the change from Baseline 
in serum Transthyretin (TTR) concentration, modified Neuropathy 
Impairment Score +7 (mNIS+7), and Norfolk Quality of Life Questionnaire-
Diabetic Neuropathy (Norfolk QOL-DN) as compared to the historical control 
of placebo arm in the ISIS 420915-CS2 NEURO-TTR (inotersen) trial 
Secondary Objectives 
To evaluate the efficacy of ION-682884, as compared to the placebo cohort in 
the NEURO-TTR trial, based on the change from Baseline in:  
• 
Neuropathy Symptom and Change (NCS) score 
• 
Physical Component Summary (PCS) score of 36-Item Short Form 
Survey (SF-36)  
• 
Polyneuropathy disability (PND) score  
• 
Modified body mass index (mBMI)  
Additional/ 
Exploratory Objectives 
To evaluate the efficacy of ION-682884 in mNIS+7 at Week 85, compared to 
Baseline. 
To evaluate the efficacy of ION-682884 in the Change from Baseline in the 
Patient Global Impression of Severity (PGIS) and Patient Global Impression 
of Change (PGIC) at Weeks 37 and 85. 
To evaluate the efficacy of ION-682884, as compared to the historical control 
of the placebo arm in the ALN-TTR02-004 trial (APOLLO trial, 
ClinicalTrials.gov Identifier:  NCT01960348) in:  
• 
Change from Baseline in Norfolk QOL-DN at Week 85  
• 
Change from Baseline in 10-Meter Walk Test (10MWT)  
• 
Change from Baseline in Rasch-built Overall Disability Score (R-ODS) 
• 
Change from Baseline in Composite Autonomic Symptom Score-31 
(COMPASS-31)   
• 
Change from Baseline in 5 Level EQ-5D (EQ-5D-5L) 
To evaluate the efficacy of ION-682884, as compared to the placebo cohort in 
the NEURO-TTR trial, in: 
• 
Change from Baseline in the SF-36  
• 
Frequency of all-cause hospitalizations (in all patients and in patients 
with cardiac involvement) 
• 
Change from Baseline in transthoracic echocardiogram (ECHO) 
parameters including left ventricular (LV) mass, LV wall thickness, 
intraventricular septum (IVS) thickness, global longitudinal strain 
(GLS), in patients with cardiac involvement  
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PROTOCOL SYNOPSIS CONTINUED 
Additional/ 
Exploratory 
Objectives Continued 
• 
Change from Baseline in N-terminal pro b-type natriuretic peptide 
(NT-proBNP) in patients with cardiac involvement 
To evaluate the plasma trough and post-treatment concentrations of 
ION-682884 or inotersen in all patients, and to evaluate plasma 
pharmacokinetic (PK) parameters in a subset of patients. 
Safety Objectives 
To evaluate safety and tolerability of ION-682884 in hATTR-PN patients, 
in the following measures:  change from Baseline in platelet count and renal 
function, adverse events, vital signs and weight, physical examination 
findings, clinical laboratory tests, electrocardiogram (ECG) parameters, use 
of concomitant medication, thyroid panel tests, inflammatory panel tests, 
coagulation tests, and immunogenicity tests. 
Study Design 
This is a multicenter, open-label study with historical controls and an active 
reference arm (inotersen).  Approximately 140 patients will be randomized 
6:1 to receive subcutaneous (SC) injections of either ION-682884 
 
once every 4 weeks or inotersen 
 once a week.  Patients will also 
take daily supplemental doses of the recommended daily allowance of 
vitamin A.  
An interim analysis will be conducted at Week 35.  Primary endpoint (PEP) 
analysis will be performed at Week 66.  
Patients included in the inotersen reference arm will be crossed over to 
ION-682884 at Week 37 after completing the Week 35 assessments.  
All patients will continue dosing with ION-682884 until Week 81 with 
end-of-treatment (EOT) assessments at Week 85, 4 weeks after the last 
dose.   
At Week 35, an interim analysis will be performed in hierarchical order for 
the following 3 efficacy endpoints:  1) serum TTR reduction; 2) mNIS+7; 
3) Norfolk QOL-DN.  
At Week 66, co-primary endpoints will be:  1) serum TTR reduction; 
2) mNIS+7; 3) Norfolk QOL-DN. 
Following treatment and the EOT assessments, 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 authorities. All participating patients in the 
OLE study will continue to receive ION-682884 once every 4 weeks.  
Patients not participating in the OLE will enter the 20-week post-treatment 
evaluation portion of this study after completing the EOT assessments. 
A Data and Safety Monitoring Board (DSMB) will be established to review 
safety, tolerability and efficacy data (as needed) collected during this study, 
both individual events and aggregate data.   
 
 
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PROTOCOL SYNOPSIS CONTINUED 
Number of Patients 
Approximately 140 patients will be enrolled into this study 
Study Population 
To be eligible to participate in this study candidates must meet the following 
eligibility criteria within 10 weeks of Study Day 1, or at the time point specified 
in the individual eligibility criterion listed. 
The Sponsor Medical Monitor may be consulted if any questions arise regarding 
the inclusion or exclusion criteria. 
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 to 82 years at the time of informed consent 
3. 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 highly effective contraceptive methods (refer to Section 6.3.1) 
from the time of signing the informed consent form until at least 
24 weeks after the last dose of ION‑682884 or inotersen and 
agree to receive a monthly pregnancy test 
b. Males:  Surgically sterile (i.e., bilateral orchidectomy) or, if engaged in 
sexual relations with a woman of child-bearing potential (WOCBP), the 
patient or the patient’s non-pregnant female partner must use a highly 
effective contraceptive method (refer to Section 6.3.1) from the time of 
signing the informed consent form until at least 24 weeks after the last 
dose of ION‑682884 or inotersen. 
* 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. 
 
 
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PROTOCOL SYNOPSIS CONTINUED 
Study Population 
Continued 
Inclusion Criteria Continued 
4. hATTR-PN as defined by meeting all 3 of the following criteria: 
a. Stage 1 (ambulatory without assistance) or Stage 2 (ambulatory with 
assistance) according to the Familial Amyloid Polyneuropathy (FAP) 
or Coutinho Stage  
b. Documented genetic mutation in the TTR gene 
c. Symptoms and signs consistent with neuropathy associated with 
transthyretin amyloidosis, including NIS ≥ 10 and ≤ 130 
5. Willingness to adhere to vitamin A supplementation per protocol 
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. 
Screening laboratory results as follows, or any other clinically significant 
abnormalities in screening laboratory values that would render a patient 
unsuitable for inclusion: 
a. Urine protein/creatinine ratio (UPCR) ≥ 1000 mg/g.  In the event of 
UPCR above this threshold, eligibility may be confirmed by a repeat 
random urine test with UPCR < 1000 mg/g or a quantitative total urine 
protein measurement of < 1000 mg/24 hr 
b. Renal insufficiency as defined by estimated glomerular filtration rate 
(eGFRcreat-cys) < 45 mL/min/1.73 m2 at Screening (eGFRcreat-cys is 
calculated using the Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] creatinine-cystatin C equation from 2012) 
(Inker et al. 2012) 
c. Positive test for blood (including trace) on urinalysis that is 
subsequently confirmed with urine microscopy showing > 5 red blood 
cells per high power field and is related to glomerulopathies.  In 
women, this exclusion criterion must be assessed outside of menstrual 
period.  If in the opinion of the Investigator the hematuria is not 
considered related to glomerulopathies the patient may be considered 
eligible, pending proper follow-up and a discussion with the medical 
monitor.  Patients with history of bladder cancer must have been 
treated with curative intent and have not presented recurrence within 
the prior 5 years. 
d. Alanine aminotransferase/ aspartate aminotransferase 
(ALT/AST) > 2 × upper limit of normal (ULN) 
e. Bilirubin ≥ 1.5 × ULN (patients with bilirubin ≥ 1.5 × ULN may be 
allowed on study if indirect bilirubin only is elevated, ALT/AST is not 
greater than the ULN and known to have Gilbert’s disease) 
f. Platelets < 125 × 109/L 
g. HbA1C ≥ 7% 
h. Abnormal thyroid function tests with clinical significance per 
Investigator judgement  
 
 
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PROTOCOL SYNOPSIS CONTINUED 
Study Population 
Continued 
Exclusion Criteria Continued 
3. Active infection requiring systemic antiviral or antimicrobial therapy that will 
not be completed prior to Study Day 1 
4. Unwillingness to comply with study procedures, including follow-up, as 
specified by this protocol, or unwillingness to cooperate fully with the 
Investigator 
5. Known history of or positive test for human immunodeficiency virus (as 
evidenced by positive tests for HIV antibody and HIV RNA), hepatitis C (as 
evidenced by positive tests for HCV antibody and HCV RNA) or hepatitis B 
(as evidenced by a positive test for hepatitis B surface antigen)  
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. Malignancy within 5 years, except for basal or squamous cell carcinoma of the 
skin, melanoma in situ, prostate carcinoma grade group 1, breast ductal 
carcinoma in situ, or carcinoma in situ of the cervix. Patients with a history of 
other malignancies who have been treated with curative intent and without 
recurrence within 5 years may also be eligible per Investigator judgement  
8. Current treatment with any approved drug for hereditary TTR amyloidosis 
such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), 
Onpattro™ (patisiran), off-label use of diflunisal, doxycycline or 
tauroursodeoxycholic acid (TUDCA).  If previously treated with Vyndaqel® / 
Vyndamax™, diflunisal or doxycycline, and TUDCA, must have 
discontinued treatment at least 2 weeks prior to Study Day 1   
9. Current or previous treatment with Tegsedi™ (inotersen) or Onpattro™ 
(patisiran) or other oligonucleotide or RNA therapeutic (including siRNA).  
This exclusion criterion does not apply to COVID-19 mRNA vaccinations.  
10. Treatment with another investigational drug, biological agent, or device 
within 3 months of screening, or 5 half-lives of study agent, whichever is 
longer 
11. History of bleeding, diathesis or coagulopathy (e.g., liver cirrhosis, 
hematologic malignancy, antiphospholipid antibody syndrome, congenital 
disorders such as hemophilia A, B, and Von Willebrand disease) 
12. Recent history of, or current drug or alcohol abuse 
13. Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to 
the first dose of ION‑682884 or inotersen and regular clinical monitoring is 
performed 
14. Karnofsky performance status ≤ 50% 
 
 
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PROTOCOL SYNOPSIS CONTINUED 
Study Population 
Continued 
Exclusion Criteria Continued 
15. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune 
disease, diabetic neuropathy) 
16. Prior liver transplant or anticipated liver transplant within 1 year of 
Screening 
17. New York Heart Association (NYHA) functional classification of ≥ 3 
18. Known immunoglobulin light chain amyloidosis (AL amyloidosis) 
19. Known leptomeningeal amyloidosis 
20. Known multiple myeloma 
21. Monoclonal gammopathy of undetermined significance (MGUS) and/or 
alterations in immunoglobulin free light chain (FLC) ratio unless fat, bone 
marrow, or heart biopsy confirming the absence of light chain and the 
presence of TTR protein by mass spectrometry or immunoelectron 
microscopy.  For patients with chronic kidney disease (CKD) and without 
presence of monoclonal protein in blood and urine, the acceptable FLC 
ratio is 0.26–2.25.  Results different from that may be discussed with local 
hematologist, Investigator and Medical Monitor if the risks associated 
with the biopsy outweigh the benefits. 
22. Presence of known type 1 or type 2 diabetes mellitus 
23. Anticipated survival less than 2 years  
24. 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 
Patients will be randomized 6:1 to receive either ION-682884 or inotersen  
ION-682884 / 
Inotersen Dosage 
and Administration 
ION-682884 will be administered once every 4 weeks 
as a SC 
injection.  Inotersen will be administered once every week 
as a 
SC injection. 
Rationale for Dose 
and Schedule 
Selection 
A dose of 
ION-682884, administered once every 4 weeks, was 
selected based on the pharmacodynamics and safety analysis of the Phase 1 
study, ION-682884-CS1.   
A dose 
of inotersen, administered weekly, was administered in the 
NEURO-TTR trial.  
Adjustment of Dose 
and/or Treatment 
Schedule 
Dose adjustments, including dose interruptions, may be allowed for safety or 
tolerability. 
Study Visit Schedule 
and Procedures 
Detailed information regarding the study procedures are outlined in Section 6 
and Appendix A and Appendix C. 
The study for an individual patient will generally consist of the following 
periods: 
• 
A ≤ 10-week Screening Period and Baseline/Day 1 
• 
An 84-week Treatment Period  
• 
A 20-week Post-Treatment Evaluation Period 
 
 
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PROTOCOL SYNOPSIS CONTINUED 
Study Visit Schedule and 
Procedures Continued 
Collection and measurement of vital signs, clinical laboratory parameters 
(including hematology, serum chemistry, and urinalysis), adverse events, 
concomitant medication/procedure information, pharmacodynamic (PD) 
parameters (TTR), ION-682884 or inotersen plasma trough and 
post-treatment concentrations, and immunogenicity testing will be 
performed according to the schedule of procedures in Appendix A.  
The following assessments will also be performed at specified visits during 
the study:  mNIS+7, Norfolk QOL-DN, mBMI/BMI, SF-36, R-ODS, 
EQ-5D-5L, COMPASS-31, 10-meter walk test, physical examination, 
PND score, and ECG.  All patients will also have a transthoracic ECHO 
conducted at Baseline, Week 35, 66, 85 and 105.  Furthermore, 
approximately 28 patients will have additional PK sampling at specified 
visits according to the schedule of procedures (Appendix A). 
ION-682884 or inotersen will be administered at the Study Center during 
scheduled clinic visits as outlined in the schedule of procedures 
(Appendix A).  Otherwise, administration of ION-682884 or inotersen may 
be given by either the Study Center personnel or at home by the 
patient/caregiver/home health-care provider.  Dosing instructions and 
training on injection technique will be provided to the patient/caregiver/ 
home health-care provider. 
Primary Endpoints 
Week 35 Interim Analysis:  Change from Baseline in serum TTR 
concentration and the mNIS+7;  
Week 66 Final Analysis:  Change from Baseline in serum TTR 
concentration, mNIS+7 and Norfolk QOL-DN 
Secondary Endpoints 
Week 35 Interim Analysis:  
• 
Change from Baseline in Norfolk QOL-DN 
Week 66 Final Analysis:  
• 
Change from Baseline in the NSC score at Weeks 35 and 66  
• 
Change from Baseline in the PCS score of SF-36 at Week 65 
• 
Change from Baseline in PND score at Week 65  
• 
Change from Baseline in mBMI at Week 65 
Additional/Exploratory 
Endpoints 
Change from Baseline in mNIS+7 at Week 85 
Change from Baseline in Norfolk QOL-DN at Week 85 
Change from Baseline in 10MWT at Weeks 37 and 81 
Change from Baseline in R-ODS at Weeks 37 and 81 
Change from Baseline in COMPASS-31 at Weeks 37 and 81 
Change from Baseline in EQ-5D-5L at Weeks 37 and 81 
Change from Baseline in the SF-36 at Week 35 
Frequency of all cause hospitalizations in all patients by Week 66 
Frequency of all cause hospitalizations in patients with cardiac involvement 
by Week 66 
 
 
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PROTOCOL SYNOPSIS CONTINUED 
Additional/Exploratory 
Endpoints Continued 
Change from Baseline in ECHO parameters, including LV mass, LV wall 
thickness, IVS thickness, and GLS, at Week 66 in patients with cardiac 
involvement 
Change from Baseline in NT-proBNP at Week 65 in patients with cardiac 
involvement 
Change from Baseline in PGIS at Weeks 37 and 85 
PGIC at Weeks 37 and 85 
Plasma trough and post-treatment concentrations of ION-682884 or 
inotersen in all patients, area under the curve (AUC), Cmax, and Tmax in a 
subset of patients, and t½λz for patients who do not roll over to the OLE 
study. 
Safety Endpoints 
Change from Baseline in platelet count per Common Terminology Criteria 
for Adverse Events (CTCAE) grade. 
Change from Baseline in renal function. 
Additional safety endpoints include:  adverse events, vital signs and weight, 
physical examination, clinical laboratory tests, ECG, use of concomitant 
medication, thyroid panel, inflammatory panel, coagulation, and 
immunogenicity. 
Statistical Considerations Sample Size 
The sample size for this study was estimated based on the data from the 
NEURO-TTR clinical trial.  With 140 patients (120 of them dosed with 
ION-682884) and assuming a 10% dropout rate, there would be 
108 evaluable patients treated with ION-682884.  In the NEURO-TTR trial, 
there are 52 evaluable placebo patients.  There would be at least 90% power 
to detect a 19.6 point difference in the change from Baseline of the mNIS+7 
score between ION-682884-treated patients and the NEURO-TTR placebo 
patients, with a 2-sided alpha level of 0.025.  
For the serum TTR percent change from Baseline, there would be at least 
95% power to detect a 70.3% difference in the percent change from 
Baseline between ION-682884-treated patients and the 
NEURO TTR-placebo patients, with a 2-sided alpha level of 0.025.   
Week 35 Interim Analysis  
The multiplicity will be controlled by using the ranking strategy in the 
following testing sequence:  
• 
Comparison of percent change from Baseline to Week 35 in serum 
TTR between ION-682884 and NEURO-TTR Placebo in the Full 
Analysis Set. 
• 
Comparison of change from Baseline to Week 35 in the mNIS+7 
between ION-682884 and NEURO-TTR Placebo in the Full Analysis 
Set. 
• 
Comparison of change from Baseline to Week 35 in the Norfolk 
QOL-DN between ION-682884 and NEURO-TTR Placebo in the Full 
Analysis Set.   
The statistical analysis will be conducted with 2-sided alpha level of 0.025.   
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PROTOCOL SYNOPSIS CONTINUED 
Statistical 
Considerations 
Continued 
The percent change in serum TTR from Baseline to Week 35 will be analyzed 
using the Mixed Effects Model with Repeated Measures (MMRM) model 
adjusted by propensity score weights. 
Week 35 Interim Analysis Continued 
For mNIS+7 and Norfolk QOL-DN, the treatment comparison at Week 35 will 
be based on the ANCOVA model adjusted by propensity score.  Patients with a 
missing mNIS+7 (or Norfolk QOL-DN) at Week 35 will have value multiply 
imputed using an imputation model. 
Week 66 Final Analysis 
The multiplicity for the final analysis will be controlled by using the ranking 
strategy in the following testing sequence:  
• 
Co-Primary Endpoint.  Comparison of percent change from Baseline to 
Week 65 in serum TTR between ION-682884 and NEURO-TTR Placebo in 
the Full Analysis Set.   
• 
Co-Primary Endpoint.  Comparison of change from Baseline to Week 66 in 
the mNIS+7 between ION-682884 and NEURO-TTR Placebo in the Full 
Analysis Set.   
• 
Co-Primary Endpoint.  Comparison of change from Baseline to Week 66 in 
the Norfolk QOL-DN between ION-682884 and NEURO-TTR Placebo in 
the Full Analysis Set.   
• 
Secondary Endpoint:  Comparison of change from Baseline to Week 66 in 
the NSC between ION-682884 and NEURO-TTR Placebo in the Full 
Analysis Set 
• 
Secondary Endpoint:  Comparison of change from Baseline to Week 35 in 
the NSC between ION-682884 and NEURO-TTR Placebo in the Full 
Analysis Set  
• 
Secondary Endpoint:  Comparison of change from Baseline in the PCS 
score of SF-36 at Week 65 between ION-682884 or NEURO-TTR Placebo 
in the Full Analysis Set  
• 
Secondary Endpoint:  Comparison of change from Baseline to Week 65 in 
the PND between ION-682884 and NEURO-TTR Placebo in the Full 
Analysis Set. 
• 
Secondary Endpoint.  Comparison of change from Baseline to Week 65 in 
mBMI between ION-682884 and NEURO-TTR Placebo in the Full 
Analysis Set  
In the Week 66 Final Analysis, the alpha level for this endpoint will be 
determined by the resampling procedure (Westfall and Young 1993).  For those 
endpoints that are not tested in the interim analysis, significance level of 0.05 will 
be used.  MMRM model adjusted by propensity score weights will be used for 
the primary and secondary analyses in the Week 66 Final Analysis.  
The reference arm with inotersen treatment will only be summarized 
descriptively 
Sponsor 
Ionis Pharmaceuticals  
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STUDY SCHEMA 
 
 
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STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
10MWT 
10-Meter Walk Test 
AE(s) 
adverse event(s) 
AESI 
adverse events of special interest  
AL amyloidosis 
amyloid light amyloidosis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANA 
antinuclear antibody 
aPTT 
activated partial thromboplastin time 
ASO(s) 
antisense oligonucleotide(s) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the curve 
Bb 
complement factor Bb (activated complement split product) 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C5a 
complement factor C5a (activated complement split product) 
Cmax  
maximum concentration 
CBC 
complete blood count 
CKD 
chronic kidney disease  
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMV 
cytomegalovirus 
COMPASS-31 
Composite Autonomic Symptom Score-31 
CRNMB 
clinically relevant, non-major bleeding events 
CTCAE 
Common Terminology Criteria for Adverse Events  
dL 
deciliter 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOT 
end-of-treatment 
eGFR 
estimated glomerular filtration rate 
eplontersen 
nonproprietary name for ION-682884 
EQ-5D-5L 
5-level EQ-5D version 
FAP 
familial amyloid polyneuropathy 
FLC 
free light chain  
GCP 
good clinical practice 
GLS 
global longitudinal strain 
hATTR-PN 
hereditary transthyretin-mediated amyloid polyneuropathy 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
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hsCRP 
c-reactive protein measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
ION-682884 
Sponsor compound code for eplontersen (antisense inhibitor of transthyretin)  
IRB 
Institutional Review Board 
ISIS-420915 
antisense inhibitor of transthyretin with generic name of inotersen and brand name 
Tegsedi™ 
IUS 
intrauterine hormone-releasing system  
IV 
intravenous(ly) 
IVS 
intraventricular septum  
IXRS 
Interactive Voice/Web-Response System 
L 
liter 
LV 
left ventricular 
m2 
square meter 
MB 
major bleeding 
mBMI 
modified body mass index (defined as body mass index in kg/m2 multiplied by 
serum albumin in g/L) 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
MGUS 
monoclonal gammopathy of undetermined significance 
MMRM 
Mixed Effects Model with Repeated Measures 
mNIS+7 
modified neuropathy impairment score plus 7 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
Norfolk QOL-DN 
Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (QOL-DN)  
NSAID 
non-steroidal anti-inflammatory drug 
NSC 
neuropathy symptom and change  
NT-proBNP 
N-terminal pro brain natriuretic peptide 
NYHA 
New York Heart Association 
OLE 
open-label extension 
OLT 
orthotopic liver transplant 
on study 
the patient is ‘on study’ from signing of the informed consent until their last study 
visit 
PCS 
physical component summary score 
PD 
pharmacodynamic 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PEP 
primary endpoint  
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic 
PND 
polyneuropathy disability score 
PT 
prothrombin time 
QOL 
quality of life 
RBP4 
retinol binding protein 4  
RDA 
recommended daily allowance  
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rINN 
recommended international nonproprietary name 
R-ODS 
Rasch-built Overall Disability Score  
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA strand in 
RNA/DNA hybrids 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SF-36 
36-Item Short Form Survey 
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
Study Day 1 
defined as the first day ION-682884 or inotersen is administered to the patient 
SUSAR 
suspected unexpected serious adverse reaction 
TME(s) 
targeted medical event(s) 
tmax  
time to maximal concentration 
TUDCA 
tauroursodeoxycholic acid 
UACR 
urine albumin to creatinine ratio  
ULN 
upper limit of normal 
UPCR 
urine protein to creatinine ratio 
USAN 
United States accepted name 
VS 
vital sign 
WBC 
white blood cell 
WOCBP 
woman of child-bearing potential 
 
 
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1. 
OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives 
1.1.1. 
Primary Objectives 
To evaluate the efficacy of ION-682884 after administration for 65 weeks, as compared to the 
historical control of the placebo cohort in the NEURO-TTR trial, based on the change from 
Baseline in serum TTR concentration, mNIS+7 and in the Norfolk Quality of Life Questionnaire-
Diabetic Neuropathy (Norfolk QOL-DN) in patients with hATTR.  
1.1.2. 
Secondary Objectives 
To evaluate the efficacy of ION-682884, as compared to the placebo cohort in the NEURO-TTR 
trial, based on the change from Baseline in the following measures:  
• Neuropathy Symptom and Change Score (NSC) 
• Physical component summary (PCS) score of 36-Item Short Form Survey (SF-36) 
• Polyneuropathy disability (PND) score 
• Modified body mass index (mBMI) 
1.1.3. 
Safety Objectives  
To evaluate safety and tolerability in hATTR-PN patients treated with ION-682884 including the 
change from Baseline in platelet count and renal function, the presence of adverse events (AEs).  
1.1.4. 
Additional/Exploratory Objectives 
1.1.4.1. 
Efficacy Objectives  
To evaluate the efficacy of ION-682884 in mNIS+7 at Week 85, compared to Baseline. 
To evaluate the efficacy of ION-682884 in the Change from Baseline in the Patient Global 
Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) at Weeks 37 
and 85.  To evaluate the efficacy of ION-682884, as compared to the historical control of the 
placebo arm included in the ALN-TTR02-004 (APOLLO trial, ClinicalTrials.gov Identifier: 
NCT01960348) in the following measures:  
• Change from Baseline in Norfolk QOL-DN at Week 85  
• Change from Baseline in 10-Meter Walk Test (10MWT) 
• Change from Baseline in Rasch-built Overall Disability Score (R-ODS) 
• Change from Baseline in Composite Autonomic Symptom Score-31 (COMPASS-31)   
• Change from Baseline in 5-level EQ-5D version (EQ-5D-5L) 
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To evaluate the efficacy of ION-682884 as compared to the placebo cohort of the NEURO-TTR 
trial in:  
• Change from Baseline in the SF-36 
• Frequency of all-cause hospitalizations (in all patients and in patients with cardiac 
involvement) 
• Change from Baseline in transthoracic echocardiogram (ECHO) parameters, 
including left ventricular (LV) mass, LV wall thickness, intraventricular septum 
(IVS) thickness, and global longitudinal strain (GLS), in patients with cardiac 
involvement 
• Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) in 
patients with cardiac involvement 
1.1.4.2. 
Pharmacokinetic Objectives 
To evaluate the plasma trough and post-treatment concentrations of ION-682884 or inotersen in 
all patients, and to evaluate plasma pharmacokinetic (PK) parameters in a subset of patients. 
1.2. 
Study Endpoints 
1.2.1. 
Interim Analysis Co-Primary Efficacy Endpoints at Week 35 
• Percent change from Baseline in serum TTR concentration at Week 35 
• Change from Baseline in mNIS+7 at Week 35 
1.2.2. 
Interim Analysis Key Secondary Efficacy Endpoint at Week 35 
• Change from Baseline in Norfolk QOL-DN at Week 35 
1.2.3. 
Final Analysis Co-Primary Efficacy Endpoints 
• Percent change from Baseline in serum TTR concentration at Week 65 
• Change from Baseline in mNIS+7 at Week 66 
• Change from Baseline in Norfolk QOL-DN at Week 66 
1.2.4. 
Final Analysis Secondary Endpoints 
• Change from Baseline in NSC at Weeks 35 and 66  
• Change from Baseline in the PCS score of SF-36 at Week 65 
• Change from Baseline in PND score at Week 65  
• Change from Baseline in mBMI at Week 65  
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1.2.5. 
Safety Endpoints  
• Change from Baseline in platelet count during the Treatment Period  
• Change from Baseline in renal function during the Treatment Period 
• Adverse events  
• Vital signs and weight  
• Physical examination  
• Clinical laboratory tests 
• Electrocardiogram (ECG) 
• Use of concomitant medication  
• Thyroid panel 
• Inflammatory panel 
• Coagulation 
• Immunogenicity 
1.2.6. 
Additional/Exploratory Endpoints 
1.2.6.1. 
Efficacy Endpoints  
• Change from Baseline in mNIS+7 at Week 85 
• Change from Baseline in Norfolk QOL-DN at Week 85 
• Change from Baseline in 10MWT at Weeks 37 and 81 
• Change from Baseline in R-ODS at Weeks 37 and 81 
• Change from Baseline in COMPASS-31 at Weeks 37 and 81 
• Change from Baseline in EQ-5D-5L at Weeks 37 and 81 
• Change from Baseline in the SF-36 components at Weeks 35 
• Frequency of all cause hospitalizations in all patients and in patients with cardiac 
involvement by Week 66  
• Change from Baseline in transthoracic ECHO parameters, including LV mass, 
LV wall thickness, IVS thickness, and GLS, in patients with cardiac involvement at 
Week 66  
• Change from Baseline in NT-proBNP in patients with cardiac involvement at 
Week 65 
• Change from Baseline in PGIS at Weeks 37 and 85 
• PGIC at Weeks 37 and 85 
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1.2.6.2. 
Pharmacokinetic Endpoints 
Plasma trough and post-treatment concentrations of ION-682884 or inotersen in all patients, area 
under the curve (AUC), Cmax, and Tmax in a subset of patients, and t½λz for patients who do not 
roll over to the open-label extension (OLE) study. 
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
2.1.1. 
Disease Background 
Hereditary transthyretin amyloidosis (hATTR) is a progressive, irreversible, and fatal disease 
caused by mutations in the gene that codes for transthyretin (TTR).  Single-point gene mutations 
destabilize the normal TTR tetrameric structure, causing its dissociation into free monomers.  
These monomers misfold and subsequently aggregate into insoluble, extracellular fibril deposits, 
causing cell degeneration and death (Quintas et al. 2001; Plante-Bordeneuve and Said 2011).  
Accumulation of amyloid deposits in hATTR occur in multiple organ systems, including the 
peripheral nervous system, gastrointestinal tract, kidney, and heart.  Due to the multiple organ 
deposition of amyloid, the disease has a wide spectrum of clinical manifestations.  However, 
historically, hATTR has been divided into 2 major phenotypes:  hATTR with polyneuropathy 
(hATTR-PN), and hATTR with cardiomyopathy (hATTR-CM). 
The global prevalence of hATTR-PN has been estimated at approximately 10,000 patients 
(range 5,526–38,468) (Coelho et al. 2008; Schmidt et al. 2018).  The main clinical 
manifestations of hATTR-PN is a progressive peripheral sensorimotor and autonomic 
neuropathy (Plante-Bordeneuve and Said 2011).  Symmetrical loss of pain and temperature 
sensitivity typically begins in the lower extremities, progressing distal to proximal.  Motor 
neuropathy follows within a few years, which affects ambulatory status (Coutinho et al. 1980; 
Sekijima et al. 2009; Plante-Bordeneuve and Said 2011).  Hereditary ATTR-PN is classified into 
3 stages (Familial Amyloid Polyneuropathy [FAP] or Coutinho Stages) based on ambulatory 
status (Coutinho et al. 1980):  Stage 1 does not require assistance with ambulation, Stage 2 
requires assistance with ambulation, and Stage 3 is wheelchair bound.  This staging system was 
used to classify severity of disease in patients being considered for enrollment in the pivotal 
study of ISIS 420915 (CS2).  Disease severity can also be assessed using the PND score, which 
is a 5-stage scoring system (Suhr et al. 1996).  Life-threatening autonomic dysfunction develops 
in many patients, affecting the cardiocirculatory, gastrointestinal, and genitourinary systems.  
Symptoms include orthostatic hypotension, which can lead to dizziness, loss of consciousness 
and frequent falls.  Gastrointestinal symptoms include diarrhea, severe constipation, alternating 
diarrhea/constipation, fecal incontinence, vomiting, and gastroparesis, all leading to 
progressive weight loss.  Genito-urinary symptoms, including recurrent urinary tract 
infections, and, in men, erectile dysfunction may be present (Plante-Bordeneuve and Said 2011).  
Lifemexpectancy of patients with hATTR-PN is reported to be 5-12 years after diagnosis 
(Adams et al. 2012; Coelho et al. 2018).  Patients typically die due to malnutrition and cachexia, 
renal failure, and cardiac disease (Coelho et al. 2008). 
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Cardiac involvement has been estimated to occur in 80% of TTR amyloidosis (Plante-
Bordeneuve and Said 2011), manifested by restrictive cardiomyopathy and heart failure (Castano 
et al. 2015), conduction abnormalities and arrhythmias.  Amyloid deposits in the kidney are 
common and can result in microalbuminuria with progression to renal failure in a subset of 
patients.  
As expected, given the severity of hATTR, there is a significant impact on patients’ and 
caregivers’ quality of life (QOL) (Stewart et al. 2013; Gertz 2017).  Caregivers have moderate to 
high levels of fatigue and spend a significant amount of time caring for patients.  Hereditary 
ATTR is associated with a substantial disruption in employment rates and work productivity.  
There is also a large mental health burden on both caregivers and patients. 
2.1.2. 
Overview of Target – Transthyretin 
The name transthyretin (TTR) is derived from transporter of thyroxine and retinol and was 
formerly known as prealbumin.  TTR is synthesized primarily in the liver and, to a lesser extent, 
by the choroid plexus and retina.  A major function of TTR in the plasma is to transport retinol 
(vitamin A) to tissues and decrease urinary clearance of retinol through its association with 
retinol binding protein 4 (RBP4).  About 70% of total body retinol is stored in the liver and 
mobilized into the blood stream bound to RBP4 (D'Ambrosio et al. 2011).  The ratio RBP4:TTR 
in plasma is around 0.3 in healthy individuals, indicating that most of the circulating TTR 
remains free of RBP4 ligand (Buxbaum and Reixach 2009).  Besides transporting the 
retinol-RBP4 complex, TTR also transports ~15% of plasma thyroxine with most of the 
thyroxine transported by either thyroxine binding globulin or albumin.  
Recent evidence has suggested that TTR may also have a neuroprotective function in the brain.  
Brain TTR is produced primarily by the choroid plexus and has been proposed to help with nerve 
regeneration and to play a protective role in the Alzheimer’s disease (Buxbaum and Reixach 
2009; Fleming et al. 2009).  It has been demonstrated that mice treated systemically with a 
TTR-specific antisense oligonucleotide (ASO) had decreased hepatic TTR mRNA levels and 
serum TTR concentration but did not show changes in the expression of TTR in the choroid 
plexus (Benson et al. 2006; Benson et al. 2017). 
2.1.3. 
Current Therapies  
Current therapeutic strategies to treat hATTR-PN include orthotopic liver transplant (OLT) 
or pharmacotherapy by stabilizing the TTR tetramers with Vyndaqel® (tafamidis) or 
off-label use of diflunisal, or by silencing the TTR protein production with Tegsedi™ (inotersen) 
or Onpattro™ (patisiran) (Coelho et al. 2012; Berk et al. 2013; Adams et al. 2016; Adams, 
Hawkins, et al. 2018; Benson et al. 2018).  
Because most of the amyloidogenic-mutated TTR is secreted by the liver, OLT results in rapid 
disappearance of mutant TTR protein from the serum.  However, wild-type TTR protein 
continues to be produced by the donor liver and can deposit in the pre-existing amyloid deposits 
in the tissues after transplantation, leading to continual disease progression and, in some cases, 
accelerating heart disease (Yazaki et al. 2000; Liepnieks and Benson 2007; Yazaki et al. 2007; 
Liepnieks et al. 2010).  Younger patients with early disease, Val30Met (V30M) mutation, and 
mild symptoms (typically Stage 1) generally experience better outcomes with OLT.  Stage 2 
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patients are often not candidates for OLT due to advanced age, cardiac involvement, or other 
health reasons (Herlenius et al. 2004; Stangou and Hawkins 2004). 
Onpattro™ (patisiran) is a double-stranded small interfering RNA (siRNA) product which also 
works by inhibiting production of TTR protein; patisiran is approved in the United States and in 
the European Union for the treatment of the polyneuropathy of hATTR in adults.  This drug is 
given intravenous (IV) every 3 weeks after patients are premedicated with high-dose 
dexamethasone.  Tegsedi™ (inotersen) is an ASO drug administered once a week SC 
(Section 2.3.4); Tegsedi™ is authorized in the European Union, US and Canada for the treatment 
of Stage 1 or Stage 2 polyneuropathy in adult patients with hATTR-PN.  
Vyndaqel® (tafamidis) which is a TTR stabilizer that works by preventing dissociation of the 
tetramer into amyloid-forming monomers, is indicated for the treatment of hATTR-PN in adult 
patients with Stage 1 polyneuropathy, and is currently approved for use in Europe, Japan, and 
several other countries.  In some countries, tafamidis is also indicated for patients with more 
advanced stages of disease (Stage 2 and/or Stage 3).  For patients with ATTR-CM in the United 
States, Vyndaqel®/Vyndamax™ (tafamidis) have been recently approved for ATTR-CM and have 
been shown to reduce all-cause mortality, and cardiac related hospitalizations due to ATTR.  
Diflunisal is a non-steroidal anti-inflammatory drug (NSAID) that also acts as a TTR tetramer 
stabilizer and is not currently approved for the treatment of hATTR.  Off-label use has been 
reported in patients with Stage 1 and Stage 2 disease (Adams et al. 2016); however, the known 
cardiovascular and renal side effects associated with the NSAID drug class may limit the use of 
this drug in older patients with hATTR-PN and concomitant cardiomyopathy and/or renal 
disease. 
Consequently, there continues to be an unmet medical need for effective, well-tolerated and 
convenient treatments that do not require additional premedication for patients with hATTR-PN 
worldwide.  
2.2. 
Therapeutic Rationale 
 
 
It should be 
noted that ASOs are highly charged hydrophilic molecules that do not cross the blood brain 
barrier (Levin et al. 2008) and thus systemic treatment with ION-682884 is not predicted to 
decrease levels of TTR in the brain.  
It is predicted that decreasing the amount of liver-derived TTR protein circulating in the plasma 
by treatment with ION-682884 will result in a decrease in the formation of TTR amyloid fibril 
deposits, and thus slow, halt or even reverse disease progression.  This strategy has been 
validated in the treatment of hATTR-PN patients through 2 recently approved drugs, 
i.e., inotersen (Benson et al. 2018) (an unconjugated 2′-MOE ASO that has the same base 
sequence as ION-682884) and patisiran (Adams, Gonzalez-Duarte, et al. 2018). 
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2.3. 
ION‑682884 
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2.3.3. 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ION‑682884 can be 
found in the Investigator’s Brochure.  A summary is included below. 
The human TTR ASO, ISIS 420915 (inotersen), identified from a broad screen of ASOs targeted 
to various regions of the human TTR pre-mRNA, was demonstrated to be potent and efficacious 
in reducing human TTR mRNA expression in the human HCC cell line HepG2.  
 ION-682884, was found to 
be significantly more potent that the unconjugated parent ASO, ISIS 420915, in inhibiting TTR 
mRNA expression in human hepatocytes in vitro (approximately 51-fold improvement in 
potency, IC50), with the potential to greatly increase the safety margins.  
The activity of ISIS 420915 has been characterized in both nonhuman primates and genetically 
modified mice.  In human TTR transgenic mice, the ED50 values for human TTR hepatic mRNA 
and plasma protein reductions were 12.0 and 18.6 mg/kg/wk, respectively, following treatment 
with ISIS 420915 for 4 weeks.  Treatment of cynomolgus monkeys with 50 mg/kg/wk 
ISIS 420915 for 12 weeks reduced TTR hepatic mRNA and plasma protein concentration by 
approximately 80%.  
ION-682884, significantly improved inhibition of human TTR hepatic mRNA and plasma 
protein concentration in human TTR transgenic mice (with 28-fold and 15-fold increase in 
potency, ED50, respectively), as compared to the unconjugated ASO, which is expected for this 
hepatocyte-expressed target.  Treatment of cynomolgus monkeys for 13 weeks with 
ION-682884 resulted in 60–70% reduction in TTR hepatic mRNA and plasma 
protein concentration.  
These results using human TTR transgenic mice strongly support GalNAc-conjugation to 
significantly increase ASO potency in inhibiting hepatic mRNA and plasma protein with lower 
doses providing the potential for improved safety. 
2.3.4. 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ION‑682884, as well as 
description of previous clinical experience with other related 2′-MOE phosphorothioate 
oligonucleotides, can be found in the Investigator’s Brochure.  A summary is included below. 
ION 682884 has been evaluated in a Phase 1, double-blind, placebo-controlled clinical trial 
(ION-682884-CS1) in healthy volunteers to assess the tolerability, safety, PK, and PD of 
multiple and single doses of ION-682884.  Four (4) cohorts of healthy volunteers were dosed at 
45 mg once every 4 weeks for 4 months (Cohort A), 60 mg once every 4 weeks for 4 months 
(Cohort E), 90 mg once every 4 weeks for 4 months (Cohort B), and 120 mg as a single dose 
(Cohort C).  Twelve (12) subjects were planned for each cohort, randomized 10:2 active drug to 
placebo, although for Cohort C only 11 subjects were enrolled (randomized 9:2).  The mean 
percent change from Baseline in serum TTR in the multiple-dose cohorts at Day 99, 2 weeks 
after the fourth and last once-monthly dose, was -85.7 with 45 mg, -90.5 with 60 mg, 
and -93.8 with 90 mg.  There were no serious adverse events (SAE), and no decrease in platelet 
count or renal function in the study.  However, ALT increase was seen (< 3 × ULN) in some of 
the subjects in the 90 mg cohort.  A clinical dosing regimen 
 administered once monthly 
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Figure 3: 
Change from Baseline in mNIS+7 over Time (ISIS 420915-CS2 Full Analysis 
Set) 
 
 
Figure 4: 
Change from Baseline in Norfolk-QOL-DN over Time (ISIS 420915-CS2 Full 
Analysis Set) 
 
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2.5. 
Benefit-Risk Assessment 
2.5.1. 
Benefit Assessment 
Administration of ION-682884 to patients may reduce the levels of mutated and wild-type TTR 
protein secreted by the liver, the primary source of TTR production and a primary organ for 
GalNAc-conjugated ASO distribution after systemic delivery.  By decreasing the amount of 
liver-derived TTR protein circulating in the plasma, ION-682884 treatment should result in 
decreased formation of TTR amyloid fibril deposits and thus slow or halt disease progression, as 
measured by specific outcome measures, including mNIS+7, Norfolk-QOL-DN, R-ODS, NSC, 
SF-36, EQ-5D-5L, and COMPASS-31. 
• mNIS+7 is a modified version of the Neuropathy Impairment Score (NIS) that has been 
used in two clinical trials in patients with hATTR-PN (Adams, Gonzalez-Duarte, et al. 
2018; Benson et al. 2018).  mNIS+7is a combination of a) NIS (motor, reflexes and 
sensory neurological evaluation), b) standardized quantitative sensory testing (heat pain 
and touch pressure at multiple body sites), c) composite nerve conduction score including 
five large fiber neurophysiological attributes, and d) autonomic function measured by the 
heart rate (HR) response to deep breathing.  
• Norfolk QOL-DN is included to assess disease specific changes in the patients’ perceived 
QOL.  This instrument is a neuropathy-specific, 5-domain tool that has been validated in 
hATTR-PN patients (Vinik et al. 2014) and used in multiple pivotal trials for novel 
therapies for ATTR.  
• Rasch-built overall disability scale (R-ODS) is a 24-item patient-reported outcome 
measure validated to measure activities of daily life in patients with inflammatory 
neuropathies (van Nes et al. 2011) and hATTR-PN (Adams, Gonzalez-Duarte, et al. 
2018). 
• Neuropathy Symptom Change (NSC) Score is a questionnaire composed of 38 questions 
that assess the presence and severity of these neuropathy symptoms (including weakness, 
loss of temperature and pain sensation, and manifestations associated with autonomic 
nervous system dysfunction).  
• SF-36 is a non-disease specific tool to assess health related QOL; it is composed of 
8 multi-item scales (35 items) assessing physical function (10 items), role limitations due 
to physical health problems (4 items), bodily pain (2 items), general health (5 items), 
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vitality (4 items), social functioning (2 items), role limitations due to emotional problems 
(3 items) and emotional well-being (5 items).  These 8 scales can be aggregated into 
2 summary measures:  Physical (PCS) and Mental (MCS) Component Summary scores.  
The 36th item, which asks about health change, is not included in the scale or summary 
scores.  
• EQ-5D-5L (The EuroQol Group) is a standardized quality of life assessment, used as a 
measure of health outcome, and composed of 5 questions in the following domains: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
• COMPASS-31 (Sletten et al. 2012) is a questionnaire composed of 31 clinically selected 
questions evaluating 6 autonomic domains (orthostatic intolerance, vasomotor, 
secretomotor, gastrointestinal, bladder, and pupillomotor).  
• PGIC is a global index that evaluates all aspects of patients' health and assesses if there 
has been an improvement or decline in clinical status; and PGIS is a global index that is 
used to rate the severity of a specific condition.  
Many patients with hATTR-PN also have hATTR-CM.  There is no widely-accepted method 
for measuring progression of cardiac disease in hATTR-CM.  However, recent studies have 
shown that strain imaging with echocardiography or MRI can detect changes within a 1-year 
time frame (Falk 2011; Benson et al. 2017).  In addition, the cardiac biomarker NT-proBNP has 
been shown to be elevated in patients with cardiac amyloidosis due to amyloid light amyloidosis 
(AL Amyloidosis) and to decline as cardiac function improves following removal of the amyloid 
forming light chain protein with chemotherapy (Palladini et al. 2006).  
2.5.2. 
Risk Assessment 
The known potential risks to study participants associated with ION-682884 are detailed in the 
Guidance to Investigator section of the Investigator’s Brochure.  Study associated potential 
safety considerations include thrombocytopenia, occurrence of glomerulonephritis, and vitamin 
A deficiency. 
Thrombocytopenia and glomerulonephritis are potential considerations based on clinical findings 
with inotersen, the unconjugated form of ION-682884, 
  
This dose is 27-fold higher exposure compared to the proposed dose of ION-682884 in the 
current study study.  Frequent platelet, urine protein/creatinine ratio (UPCR), renal and hepatic 
function monitoring as well as stopping rules will be implemented in this study (see Sections 8.5 
and 8.6).  If the platelet result is unavailable (e.g., due to hemolysis, clumping, etc.) it must be 
repeated and reviewed prior to dosing during the Treatment Period.  
Because TTR binds the retinol-RBP4 complex and prevents its excretion by the kidney, 
decreased plasma TTR concentration result in decreased circulating levels of both RBP4 and 
retinol.  This has been shown with the naturally occurring TTR Ile84 mutation that disrupts the 
TTR-RBP4-retinol complex and results in low plasma levels of retinol (Waits et al. 1995).  
Prolonged reduction of circulating retinol could result in impaired delivery of retinol to 
peripheral tissues and consequent signs and symptoms of vitamin A deficiency such as night 
blindness, xerophthalmia or retinopathy.  However, chylomicrons are believed to provide an 
alternative route of delivery of retinyl esters to peripheral tissues (Wei et al. 1995) and 
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chylomicron-delivered retinyl will not be affected by treatment with ION-682884.  Indeed, 
preclinical studies utilizing TTR null mice have shown that although the mice have only 5–7% of 
circulating retinol and RBP4 levels compared to wild-type mice, they are viable and fertile, and 
do not show any observable symptoms of vitamin A deficiency (Episkopou et al. 1993; Wei et al. 
1995).  In addition, the levels of retinol within tissues such as the liver, kidney, testis and eye 
were similar in the TTR null mouse compared with wild-type controls (Wei et al. 1995).  
Furthermore, the retinal anatomy and function in these mice has been examined in detail with 
little effect found on the retinal structure or function (Bui et al. 2001).  In addition, twins have 
been reported in the literature that have a genetic mutation in RBP4 that causes their RBP4 
protein levels to be below the lower limit of quantification and also results in very low plasma 
retinol levels (Biesalski et al. 1999).  In addition, mutations in the RBP4 gene have been 
identified in 2 teenage siblings with no detectable serum RBP and retinol levels less than 20% 
normal (Biesalski et al. 1999; Seeliger et al. 1999).  Despite the low retinol, they have normal 
retinyl esters levels, normal absorption of fat and vitamin A after a meal challenge, and they have 
mild night blindness and a modest retinal dystrophy but no pronounced effects on growth or 
other physiologic functions that are normally affected during vitamin A deficiency.  Taken 
together these findings imply that RBP4 is not essential for maintaining adequate tissue retinol 
levels.  In addition, no imbalance of vitamin A deficiency was found in the NEURO-TTR trial 
after treatment with ISIS 420915, the unconjugated form of ION-682884, compared to 
placebo-treated patients.  Nonetheless, to address the potential for impaired retinol delivery to 
tissues, in this study all patients will be required to take oral supplementation of the 
recommended daily allowance (RDA) of vitamin A (approximately 3000 IU vitamin A per day).  
In addition, an ocular questionnaires to screen for vitamin A deficiency will be performed 
periodically during the trial.  
2.5.3. 
Overall Assessment of Benefit:Risk 
Taking into account the measures taken to minimize risk to patients participating in this study, 
including frequent safety monitoring and supplementation with vitamin A, the potential risks 
identified in association with ION‑682884 are justified by the anticipated benefits that may be 
afforded to patients with hATTR-PN. 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This is a Phase 3 multicenter, open-label, randomized study of ION-682884 (eplontersen) in 
Stage 1 and Stage 2 hATTR-PN patients with a NIS of 10 to 130, with a concurrent reference 
arm of inotersen.  Approximately 140 patients will be randomized 6:1 (ION-682884:inotersen) to 
receive 
 ION-682884 SC once every 4 weeks 
 or inotersen 
 SC once 
every week 
  Patients enrolled in the ION-682884 arm will be compared to patients 
enrolled in the placebo-cohort group in the ISIS 420915-CS2 (NEURO-TTR).  An interim 
analysis will be conducted at Week 35 with primary efficacy analysis at Week 66.  As both 
analyses will utilize comparisons to a control group external to the current study, the concurrent 
inotersen reference arm (n = 20) is intended to ensure that no gross differences in patient 
population and response exist between the NEURO-TTR and the current study.  Patients in the 
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reference arm (inotersen) will be crossed over to ION-682884 once they complete 
Week 35 assessments.  These patients will start ION-682884 at Week 37.  All patients will 
continue dosing with ION-682884 until Week 81 with end-of-treatment (EOT) assessments at 
Week 85, 4 weeks after the last dose.  
For patients randomized to ION-682884, attempts will be made to mirror NEURO-TTR 
distribution of patients according to disease stage (i.e., Stage 1-FAP vs. Stage 2-FAP). 
Approximately 28 patients at selected sites (~22 on ION-682884 and ~6 on inotersen) will be 
enrolled in a PK subgroup and will receive additional sampling for PK as specified in the 
Schedule of Procedures (Appendix A).  
Following treatment and the EOT assessments, eligible patients may elect to enroll in an OLE 
study pending study approval by the IRB/IEC and the appropriate regulatory authorities.  All 
participating patients in the OLE study will continue to receive ION-682884 once every 4 weeks.  
Patients not participating in the OLE will enter the 20-week post-treatment evaluation portion of 
this study after completing the EOT assessments. 
3.2. 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3. 
Number of Patients 
Approximately 140 patients will be randomized 6:1 (ION-682884:inotersen) to receive 
 
ION-682884 SC once every 4 weeks or inotersen 
 SC once weekly.  For details about the 
rationale followed to determine the number of patients required see Section 10.2.  
3.4. 
Overall Study Duration and Follow-up 
This study will consist of the following periods:  
• A ≤ 10-week Screening Period and Baseline/Day 1 Assessments 
• A 84-week Treatment Period  
• A 20-week Post-Treatment Evaluation Period/or enrollment into OLE study  
Please refer to the Schedule of Procedures in Appendix A.  Patients may be required to attend 
additional visits for monitoring of AE or abnormal investigation results.  The frequency of 
additional monitoring will be determined after consultation between the Study Medical Monitor 
and the Investigator. 
3.4.1. 
Screening and Baseline Assessment 
Patient eligibility for the study will be determined within 10 weeks prior to study entry.  The 
Baseline assessments should ideally be conducted after patient eligibility has been determined.  
3.4.2. 
Treatment Period 
The treatment and EOT Efficacy Assessment Period comprise approximately 84 weeks in total.  
Eligible patients will report to the Study Center for assessments at regular intervals throughout 
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the 80-week Treatment Period (Week 1 to Week 81).  During the Treatment Period, ION-682884 
is administered by SC injections every 4 weeks, and inotersen is administered by SC injection 
every week until Week 35.  At Week 37, patients in the inotersen arm will be crossed-over to 
ION-682884.  After the Treatment Period is complete, patients will report to the Study Center 
during Week 85 for the EOT efficacy assessments.  
3.4.3. 
Post-Treatment Evaluation Period and Long-Term Follow up 
Patients must complete follow-up visits on Weeks 89, 93, 97, 101 and 105; the visits on Weeks 
93 and 105 are mandatory in-clinic visits.  The final study visit will be on Week 105.  
Alternatively, after completion of the EOT Efficacy Assessment Period, eligible patients 
(including patients that initially received inotersen) may elect to enroll in an OLE study where 
they will receive ION-682884 once every 4 weeks, pending study approval by the IRB/IEC and 
appropriate regulatory authority.  In this case, patients will not participate in the Post-Treatment 
Evaluation Period. 
3.5. 
End-of-Study 
The Primary Completion Date, defined as “the date on which the last participant in a clinical 
study was examined or received an intervention/treatment to collect final data for the primary 
outcome measures” is the last patient Week 66 study visit.  
The Study Completion Date is the last patient last visit (Week 105) at the end of the 
Post-treatment Evaluation Period.  
3.6. 
Data and Safety Monitoring Board  
A Data and Safety Monitoring Board (DSMB) will be assembled and meet periodically to review 
safety, tolerability and efficacy data collected on ION‑682884 and inotersen, and to review the 
results of the predetermined interim analysis at Week 35.  Based on its assessment of the safety, 
tolerability and efficacy of ION‑682884 and inotersen, 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 data are outlined 
in the DSMB Charter and Statistical Analysis Plan (SAP).   
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 facing 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.  At the time of randomization, 
patients will be assigned a unique patient identification number.  This number will be used to 
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identify the subject throughout the trial and must be used on all study documentation related to 
that subject.  The screening number and patient identification number must remain constant 
throughout the entire trial.  In the event the subject is re-consented and re-screened the subject 
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 Section 5.2.  No patient 
may begin treatment prior to randomization and assignment of a unique patient identification 
number. 
Using an Interactive Voice/Web-Response System (IXRS), eligible patients will be randomized 
6:1 to receive ION-682884 or inotersen, respectively.  Attempts will be made to mirror the 
NEURO-TTR distribution of patients according to disease stage (i.e., Stage 1-FAP vs. 
Stage 2-FAP). 
4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced.   
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 10 weeks of Study Day 1, or at the time point specified in the individual eligibility 
criterion listed.  The Sponsor Medical Monitor may be consulted if any questions arise regarding 
the inclusion or exclusion criteria. 
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 to 82 years at the time of informed consent 
3. 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 
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iv. 
If engaged in sexual relations of child-bearing potential, agree to use highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of signing 
the informed consent form until at least 24 weeks after the last dose of 
ION‑682884 or inotersen and agree to receive a once every 4 weeks pregnancy 
test 
b. Males:  Surgically sterile (i.e., bilateral orchidectomy) or if engaged in sexual 
relations with a woman of child-bearing potential (WOCBP), the patient or the 
patient’s non-pregnant female partner must use a highly effective contraceptive 
method (refer to Section 6.3.1) from the time of signing the informed consent form 
until at least 24 weeks after the last dose of ION‑682884 or inotersen. 
* 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. 
4. hATTR-PN as defined by meeting all 3 of the following criteria:  
a. Stage 1 (ambulatory without assistance) or Stage 2 (ambulatory with assistance) 
according to the Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage 
b. Documented genetic mutation in the TTR gene 
c. Symptoms and signs consistent with neuropathy associated with transthyretin 
amyloidosis, including NIS ≥ 10 and ≤ 130 
5. Willingness to adhere to vitamin A supplementation per protocol 
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. Screening laboratory results as follows, or any other clinically significant abnormalities 
in screening laboratory values that would render a patient unsuitable for inclusion: 
a. Urine protein/creatinine ratio (UPCR) ≥ 1000 mg/g.  In the event of UPCR above this 
threshold, eligibility may be confirmed by a repeat random urine test with UPCR 
< 1000 mg/g or a quantitative total urine protein measurement of < 1000 mg/24 hr 
b. Renal insufficiency as defined by estimated glomerular filtration rate (eGFRcreat-cys) 
< 45 mL/min/1.73 m2 at Screening (eGFRcreat-cys is calculated using the Chronic 
Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine-cystatin C 
equation from 2012) (Inker et al. 2012) 
c. Positive test for blood (including trace) on urinalysis that is subsequently confirmed 
with urine microscopy showing > 5 red blood cells per high power field and is related 
to glomerulopathies.  In women, this exclusion criterion must be assessed outside of 
menstrual period.  If in the opinion of the Investigator the hematuria is not considered 
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related to glomerulopathies the patient may be considered eligible, pending proper 
follow-up and a discussion with the medical monitor.  Patients with history of bladder 
cancer must have been treated with curative intent and have not presented recurrence 
within the prior 5 years. 
d. Alanine aminotransferase/ aspartate aminotransferase (ALT/AST) > 2 × upper limit 
of normal (ULN) 
e. Bilirubin ≥ 1.5 × ULN (patients with bilirubin ≥ 1.5 × ULN may be allowed on study 
if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN and 
known to have Gilbert’s disease) 
f. Platelets < 125 × 109/L  
g. HbA1C ≥ 7% 
h. Abnormal thyroid function tests with clinical significance per Investigator judgement  
3. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
4. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
5. Known history of or positive test for human immunodeficiency virus (as evidenced by 
positive tests for HIV antibody and HIV RNA), hepatitis C (as evidenced by positive 
tests for HCV antibody and HCV RNA) or hepatitis B (as evidenced by a positive test for 
hepatitis B surface antigen) 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, 
melanoma in situ, prostate carcinoma grade group 1, breast ductal carcinoma in situ, or 
carcinoma in situ of the cervix.  Patients with a history of other malignancies who have 
been treated with curative intent and without recurrence within 5 years may also be 
eligible per Investigator judgement. 
8. Current treatment with any approved drug for hereditary TTR amyloidosis such as 
Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran), 
off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA).  
If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and 
TUDCA, must have discontinued treatment for 2 weeks prior to Study Day 1   
9. Current of previous treatment with Tegsedi™ (inotersen) or Onpattro™ (patisiran) or other 
oligonucleotide or RNA therapeutic (including siRNA).  This exclusion criterion does not 
apply to COVID-19 mRNA vaccinations. 
10. Treatment with another investigational drug, biological agent, or device within 3 months 
of screening, or 5 half-lives of study agent, whichever is longer 
11. History of bleeding, diathesis or coagulopathy (e.g., liver cirrhosis, hematologic 
malignancy, antiphospholipid antibody syndrome, congenital disorders such as 
hemophilia A, B, and Von Willebrand disease) 
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12. Recent history of, or current drug or alcohol abuse.  
13. Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first 
dose of ION‑682884 or inotersen and regular clinical monitoring is performed 
14. Karnofsky performance status ≤ 50% 
15. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease, 
diabetic neuropathy) 
16. Prior liver transplant or anticipated liver transplant within 1 year of Screening 
17. New York Heart Association (NYHA) functional classification of ≥ 3 
18. Known immunoglobulin light chain amyloidosis (AL amyloidosis) 
19. Known leptomeningeal amyloidosis 
20. Known multiple myeloma 
21. Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations in 
immunoglobulin free light chain (FLC) ratio, unless fat, bone marrow, or heart biopsy 
confirming the absence of light chain and the presence of TTR protein by mass 
spectrometry or immunoelectron microscopy.  For patients with CKD and without 
presence of monoclonal protein in blood and urine, the acceptable FLC ratio is 0.26-2.25.  
Results different from that may be discussed with local hematologist, Investigator and 
Medical Monitor if the risks associated with the biopsy outweigh the benefits.  
22. Presence of known type 1 or type 2 diabetes mellitus 
23. Anticipated survival less than 2 years 
24. Have any other conditions, which, in the opinion of the Investigator would make the 
patient unsuitable for inclusion, or could interfere with the subject 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 and Baseline Assessments 
Before any study-specific procedures or evaluations are initiated, patients must sign and date the 
informed consent form.  If required, the informed consent may be administered remotely using 
locally accepted methods.  An up to 10-week period is given to perform the screening 
evaluations and Baselines assessments.  An abnormal screening result may be retested if 
Investigator believes and documents that the results are artifactual.  An NIS assessment is 
performed at screening to determine patient eligibility only.  This assessment does not include 
the +7 components.  TTR genotyping is only conducted if previous results are not already 
available. 
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Baseline assessments can be conducted during the 10-week screening window and should ideally 
be performed after patient eligibility has been determined.  Appendix A details which Baseline 
assessments should be completed before Study Day 1.   
Laboratory collections can be performed by a home health-care provider instead of in-clinic.  
Biopsy for verification of amyloid deposition is not required as part of the eligibility but can be 
performed per Investigator judgment. 
The study site will record patient’s basic personal details, including name, contact details, 
gender, date of birth, age, and self-reported ethnicity and racial origin (to be used only for 
clinical purposes), as well as information on each patient’s medical history, and clinical data 
collected about his/her participation in the study. 
The 2 mNIS+7 assessments must be performed within 21 days prior to the first dose of 
ION-682884 or inotersen (Day 1) and the second mNIS+7 assessment must be conducted 
≥ 1 day apart from the first assessment.  In addition, every effort should be made to conduct the 
2 assessments < 7 days apart.  If a blood draw is to be performed on a mNIS+7 assessment day, 
they must be performed after the mNIS+7 assessment is complete.  The mNIS+7 assessment 
procedure includes the NIS, sensory and motor nerve conduction testing, quantitative sensory 
testing and measurement of heart-rate variation with breathing.  The NSC score is collected 
during the NIS assessment procedure but is analyzed separately. 
6.1.2. 
Day 1/Randomization 
During the Day 1 study visit, patients will report to the Study Center for evaluations, 
randomization, and ION‑682884 or inotersen administration (first dosing should be the last 
procedure of Day 1 study visit).  See Appendix A for the assessments that should be performed 
on Day 1.   
For a visit where Norfolk QOL-DN is to be administered, it must be the first assessment 
performed at the visit.  Baseline Norfolk QOL-DN can be administered on the same day as the 
first mNIS+7 assessment, but must be performed prior to the mNIS+7 assessment. 
For an individual patient, every effort should be made to ensure the same mNIS+7 evaluator 
performs all of the mNIS+7 assessments throughout the study.  In addition, the mNIS+7 
evaluator must be insulated from the patient’s general study procedures and knowledge of the 
patient’s AEs.  
6.1.3. 
Treatment Period 
During Study Week 1, patients will report to the Study Center for evaluations and ION-682884 
or inotersen administration on Day 1.  After Week 1, ION-682884 will be administered once 
every 4 weeks through the end of the Treatment Period.  Inotersen will be administered once 
weekly up to and including Week 34 at which time patients will transition to every 4 week 
administration of ION-682884. 
For patients randomized to the ION-682884 treatment arm, there will be a total of 43 visits 
during Weeks 1- 83 for ION-682884 administration and other study procedures (see Schedule of 
Procedures in Appendix A).  Eleven of the 43 visits are mandatory in-clinic visits, whereas 
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32 visits can be completed either in-clinic, at home by a home health-care provider (if approved 
locally), or by using a local laboratory upon Investigator approval. 
For patients randomized to the inotersen reference arm, there will be a total of 60 visits during 
Weeks 1-83 for Study Drug administration and other study procedures (see Schedule of 
Procedures in Appendix A).  Eleven of the 60 visits are mandatory in-clinic visits, whereas 
49 visits can be completed either in-clinic, at home by a home health-care provider (if approved 
locally), or by using a local laboratory upon Investigator approval. 
During an clinic visit, all blood samples should be drawn prior to ION-682884 or inotersen 
administration (exceptions are the post-dose samples in the PK subgroup).  ION-682884 or 
inotersen may be administered by either Study Center personnel (during a clinic visit) or at home 
by the patient/caregiver/home health-care provider (See Section 8.1).  Dosing instructions and 
training will be provided to the patient on Day 1 and to any caregiver, as needed. 
For patients in the inotersen treatment arm, the last inotersen dose will be at Week 34.  On 
Weeks 35 and 36 there is no dosing with inotersen.  Patients in the inotersen treatment arm will 
complete the Week 35 assessments and then cross over to ION-682884 once-every-4-weeks 
treatment starting at Week 37. 
In addition to ION-682884 or inotersen, patients will also take daily supplemental doses of the 
RDA of vitamin A (approximately 3000 IU vitamin A or similar dose as available in the region 
in which the patient resides).  Vitamin A may be taken as either a single vitamin A supplement, 
or as part of a multivitamin.  The vitamin A supplement should be taken throughout the 
Treatment and Post-Treatment Evaluation Period.  Vitamin A supplement at doses more than the 
RDA is not recommended.   
Vitamin A deficiency will be monitored by having the patient periodically complete a vitamin A 
deficiency screening questionnaire (called “ocular questionnaire”).  In cases of suspected 
vitamin A deficiency, a consultation with ophthalmologist may be requested by the Investigator, 
if deemed necessary, after discussing with the Medical Monitor. 
For Weeks 35, 37, 65 and 66 there is a ± 10 days window; for all other visits, there is a ± 7 days 
window.  All reasonable attempts should be made to ensure compliance with the visit schedule as 
outlined in the Schedule of Procedures (Appendix A).  However, in the event that a visit does not 
occur or is delayed, all subsequent visits should be calculated based on the time elapsed since 
Day 1 rather than from the date of the previous visit.   
Patients randomized to the ION-682884 treatment arm will have their platelet count, eGFR, 
UPCR, and LFTs assessed once every 4 weeks during the Treatment Period.   
Patients randomized to the inotersen reference arm will have their platelet count, eGFR, UPCR, 
and LFTs assessed every 2 weeks during the Treatment Period up to and including Week 34.  
After Week 34, patients assigned to the inotersen reference arm will transition to receive 
ION 682884 through the end of the Treatment Period.  After patients in the inotersen reference 
arm transition to ION-682884, they will continue to have every 2-week platelet count, eGFR, 
UPCR, and LFTs measurements for 8 weeks after their last dose of inotersen.  They will then be 
assessed every 4 weeks for platelet count, eGFR, UPCR, and LFTs through the end of the 
Treatment Period.   
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The window for blood collections that occur outside clinic visits is ± 4 days.  See Section 8.5 for 
guidance on ION-682884 or inotersen dosing relative to hematology and chemistry monitoring.  
Key efficacy endpoints (serum TTR reduction, mNIS+7, Norfolk QOL-DN) will be assessed at 
3 landmark visits (Weeks 35, 66, and 85).  Patients will be encouraged to complete these visits 
even if on dose pause or if treatment has been permanently discontinued prematurely. 
6.1.4. 
End-of-Treatment Assessment Visit   
The EOT efficacy assessments are conducted at Week 85 and should be performed within 
28 days from the last dose of ION-682884.  For those who do not complete dosing, please see 
Section 8.8 for guidance on follow-up procedures. 
6.1.5. 
Post-Treatment Evaluation Period 
After completion of the EOT efficacy assessment, patients will complete the Post-Treatment 
Evaluation Period which consists of 5 study visits on Weeks 89, 93, 97, 101 and 105, as outlined 
in the schedule of procedures (Appendix A).  Alternatively, after completion of the EOT efficacy 
assessment, eligible patients may elect to receive ION-682884 in an OLE study, pending study 
approval by the IRB/IEC and the appropriate regulatory authority.  In this case, patients will not 
participate in the Post-Treatment Evaluation Period. 
6.2. 
Laboratory Assessments  
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B.  All patients will be required to fast for 8–10 hours before assessment 
of retinyl palmitate (Weeks 1, 13, 25, 37, 49, 65, 85, 93, and 105).  Collection of laboratory 
samples for assessment of serum vitamin A levels should precede the ingestion of vitamin A or 
multivitamin supplement for that day (Screening/Baseline, Weeks 1, 13, 25, 37, 49, 65, 85, 93, 
and 105).  During this time, the patient can drink water and they should ensure that they do not 
become dehydrated. 
If the results of these assessments are uninterpretable (e.g., missing sample, hemolysis) the 
Investigator should request a new test as soon as possible.  If evaluable results for platelets, 
eGFR or UPCR are not available for the Investigator to review by the date of administration of 
the Study Drug, or the results are from an assessment older than 14 days ±7 days from the dosing 
day (±7 days allows for visit window), the patient should be instructed to hold dosing until the 
new results are available and interpretable.  Note:  if there are 2 sets of lab value results within 
the previous 14 days ±7 days of the dosing day, the most recent one should be used for deciding 
whether dose administration should proceed.  Please see Section 8.5 for more detail. 
6.3. 
Restriction on the Lifestyle of Patients 
6.3.1. 
Contraception Requirements 
All male patients and WOCBP must refrain from sperm/egg donation and either be abstinent† or 
use highly effective contraception from the time of signing the informed consent form until at 
least 24 weeks after their last dose of study treatment.  
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For male patients engaged in sexual relations with a WOCBP, the patient or the patient’s 
non-pregnant female partner must use a highly effective contraception method from the time of 
signing the informed consent form until at least 24 weeks after their last dose of ION-682884 or 
inotersen.  Male patients with partners that are pregnant must use condoms to ensure that the 
fetus is not exposed to the ION-682884 or inotersen. 
For the purposes of this study, WOCBP are defined as any female who has experienced 
menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age 
or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post-hysterectomy 
For the purposes of the study, highly effective contraception is defined as follows: 
For male patients: 
• Highly effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the non-pregnant female partner of WOCBP uses a highly 
effective contraceptive method (defined below) 
• Male patients with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the ION-682884 or inotersen 
For female patients and female partners of male patients, highly effective female contraception 
methods comprise: 
• Surgical sterilization (e.g., bilateral tubal occlusion), hormonal contraception 
associated with inhibition of ovulation (combined estrogen and progestogen 
containing), intrauterine contraception device or intrauterine hormone-releasing 
system (IUS) 
†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 two can result in either or both products failing. 
6.3.2. 
Other Requirements 
All patients will be required to fast for 8–10 hours before assessment of retinyl palmitate 
(Weeks 1, 13, 25, 37, 49, 65, 85, 89, 93, and 105.  Collection of laboratory samples for 
assessment of serum vitamin A levels should precede the ingestion of vitamin A or multivitamin 
supplement for that day (Screening/Baseline, Weeks 1, 13, 25, 37, 49, 65, 85, 89, 93, and 105).  
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All other blood tests performed on those weeks can be done on samples collected while 
non-fasting.  
7. 
ION-682884 / ISIS 420915 (INOTERSEN) 
ION‑682884 and inotersen characteristics are listed in Table 1.   
7.1. 
ION-682884 / ISIS 420915 Description 
7.1.1. 
ION‑682884 (Eplontersen) 
ION-682884 
storage and 
preparation instructions will be provided by the Sponsor.  ION-682884 must be stored securely 
and be protected from light. 
7.1.2. 
ISIS 420915 (Inotersen) 
ISIS 420915, 
storage and 
preparation instructions will be provided by the Sponsor.  ISIS 420915 must be stored securely  
and be protected from light.  
Table 1:  
ION-682884 / ISIS 420915 (Inotersen) Characteristics 
ION-682884 / Inotersen 
ION-682884 
ISIS 420915 (Inotersen) 
Strength 
 
  
Volume/Formulation 
 
 
Administration 
SC once every 4 weeks 
SC once every week 
  
7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged ION-682884 and inotersen labeled in 
accordance with specific country regulatory requirements.  
7.3. 
ION-682884 / ISIS 420915 (Inotersen) Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of 
ION‑682884 or ISIS 420915 supplies provided by the Sponsor according to Sponsor instructions 
and in accordance with institutional policy. 
8. 
TREATMENT OF PATIENTS 
8.1. 
ION-682884 / ISIS 420915 (Inotersen) Administration 
ION-682884 and inotersen will be provided for single use only.  ION-682884 and inotersen will 
be administered by SC injection.  
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ION-682884 or inotersen can be administered in the clinic during clinic visits per protocol or 
administered at home by the patient/caregiver/home health-care provider after clinic visits.  For 
weeks that do not include a clinic visit, ION-682884 or inotersen may be administered by either 
Study Center personnel (in which case additional clinic visits will occur) or at home by the 
patient/caregiver/home health-care provider.  Dosing instructions and training will be provided to 
the patient on Day 1 and as needed. 
Weekly inotersen administration has a window of ± 4 days.  Once-every-4-weeks ION-682884 
administration has a window of ± 7 days. 
Please refer to the ION-682884 and inotersen manuals provided by the Sponsor for more detailed 
instructions for ION-682884 and inotersen preparation and administration. 
Table 2:  
ION-682884 / ISIS 420915 (Inotersen) Dosing Information 
Study Drug 
Volume to Administer 
Total Dose 
ION-682884 
  
 
ISIS 420915 (Inotersen) 
  
  
 
8.2. 
Other Protocol-Required Drugs 
All study participants will take daily oral supplemental doses of the RDA of vitamin A 
(approximately 3000 IU vitamin A or the closest approximate dose as available in the region in 
which the patient resides).  Commercially available vitamin A as a single supplement, or as part 
of a multivitamin, should be taken by the patient, in accordance with local regulatory 
requirements and availability. 
8.3. 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures.  
8.4. 
Treatment Precautions 
There are no specific treatment precautions required for this study.  
8.5. 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring for liver chemistry tests, renal parameters, and platelet 
count, “Baseline” is defined as: 
• The average of the pre-dose test closest to Day 1 and Day 1.  The window for blood 
collections (hematology and chemistry) that occur outside clinic visits is ± 4 days 
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. 
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Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 
initial measurement) on new specimens.  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  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 ION‑682884 or inotersen. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
below (refer to Section 8.6.1 through Section 8.6.3) are met, the patient will be permanently 
discontinued from further treatment with ION‑682884 or inotersen, evaluated fully as outlined 
below and in consultation with the Sponsor Medical Monitor or appropriately qualified designee, 
and will be followed up in accordance with Section 8.8 of the protocol.   
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline, please refer to 
guidance in Section 8.5 above. 
Monitoring frequency will be once every 4 weeks in patients randomized to the ION-682884 
treatment arm until the end of the Treatment Period.   
Patients randomized to the inotersen reference arm will have their liver chemistry assessed every 
2 weeks during the Treatment Period up to and including Week 34.  After patients in the 
inotersen reference arm transition to ION-682884 they will continue to have every 2 week liver 
chemistry measurements for 8 weeks after their last dose of inotersen.  They will then be 
assessed every 4 weeks, through the end of the Treatment Period.   
For inotersen patients who terminate treatment before the end of the Treatment Period, liver 
chemistry measurements should be monitored once every 2 weeks, for a duration of 8 weeks.   
In the event of an ALT or AST measurement that is > 3 × ULN (or 2 × Baseline value if the 
Baseline value was > ULN) at any time during the study (Treatment or Post-Treatment Period), 
repeat testing should be performed within 48 to 72 hours of liver chemistry tests (ALT, AST, 
ALP, total bilirubin and international normalized ratio [INR]) to confirm the abnormalities and to 
determine if they are increasing or decreasing.  There also should be inquiry made about 
symptoms.  Additional, confirmatory measurements should also be performed if ALT or AST 
levels increase to 5 × ULN. 
If new onset symptoms of anorexia, nausea, fatigue, right upper abdominal discomfort, vomiting 
present with unclear etiology, liver enzymes should be measured. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 × ULN 
(or 2 × Baseline value if the Baseline value was > ULN) should have their liver chemistry tests 
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(ALT, AST, ALP, INR and total bilirubin, direct and indirect bilirubin) retested 2 or 3 times 
weekly.  Frequency of retesting can decrease to once a week or less if abnormalities stabilize or 
the trial drug has been discontinued and the subject is asymptomatic (see below).  
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 × ULN (or 2 × Baseline value if the Baseline value was > ULN), the following 
evaluations should be included in the work up: 
• Obtain a more detailed history of symptoms and prior and concurrent diseases 
• Obtain further history for concomitant drug use (including nonprescription 
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 immunoglobulin M [IgM], HBsAg, HCV antibody, 
cytomegalovirus [CMV] IgM, and EBV antibody panel) 
• Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA], antismooth 
muscle antibody, type 1 anti-liver kidney microsomal antibody) 
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. 
8.5.2. 
Safety Monitoring for Renal Function 
Serum creatinine, estimated glomerular filtration rate (eGFRcreat-cys, calculated using the 
CKD-EPI creatinine-cystatin C equation [2012]), urinalysis, and UPCR should be monitored 
every 4 weeks in all patients randomized to the ION-682884 treatment arm and every 2 weeks in 
all patients randomized to the inotersen reference arm, up to and including Week 34.  After 
Week 34, patients assigned to the inotersen reference arm will transition to receive ION-682884 
through the end of the Treatment Period.  After patients in the inotersen reference arm transition 
to ION-682884, they will continue to have every 2-week measurements for 8 weeks after their 
last dose of inotersen.  They will then be assessed every 4 weeks through the end of the 
Treatment Period..   
For inotersen patients who terminate treatment before the end of the Treatment Period, renal 
function should be monitored once every 2 weeks, for a duration of 8 weeks..  
In the event of a confirmed (as described in Section 8.5) laboratory result meeting 1 or more of 
the following criteria:  
a. Creatinine clearance (eGFRcreat-cyst) decrease from Baseline > 25% 
b. UPCR > 3 × Baseline AND > 1000 mg/g 
Renal function will be monitored weekly until further work up and/or resolution per Investigator 
judgment in consultation with the Medical Monitor.  If there is further worsening in renal 
function, refer to Section 8.6.2 for guidance. 
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8.5.3. 
Safety Monitoring Rules for Platelet Count Results 
Please refer also to Table 3 and Table 4. 
Platelet count monitoring frequency will be once every 4 weeks in patients randomized to the 
ION-682884 treatment arm until the end of the Treatment Period.   
Patients randomized to the inotersen reference arm will have their platelet count assessed every 
2 weeks during the Treatment Period up to and including Week 34.  After Week 34, patients 
assigned to the inotersen reference arm will transition to receive ION-682884 through the end of 
the Treatment Period.  After patients in the inotersen reference arm transition to ION-682884, 
they will continue to have every 2-week platelet count measurements for 8 weeks after their last 
dose of inotersen.  They will then be assessed every 4 weeks for platelet count through the end of 
the Treatment Period.   
For inotersen patients who terminate treatment before the end of the Treatment Period, platelets 
should be monitored once every 2 weeks, for a duration of 8 weeks.  
The Investigator should document review of all platelet count results within 48 hours of receipt. 
For patients on ION-682884 or inotersen, if a patient’s platelet count falls to less than 
100 × 109/L but more than 75 × 109/L, then the patient’s platelet counts should be monitored 
weekly.  In case of platelet reduction to below 75 × 109/L, the platelet monitoring rules for 
ION-682884 or inotersen defined in Stopping rules (Section 8.6.3, Table 4) should be followed. 
If a patient’s platelet count falls to ≤ 50 × 109/L, the Investigator must communicate to the 
Sponsor within 24 hours of receiving the platelet result.  
Treatment should be withheld if there is no evaluable platelet count within 14 days ±7 days prior 
to the scheduled dose.  Any unreportable platelet count result must be rechecked and determined 
not to have met a stopping rule before dosing can continue.  
In the event of a platelet count < 100 × 109/L, additional laboratory investigations may be 
conducted (Table 3).   
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Table 3: 
Additional Labs to be Performed in the Event of a Platelet Count 
< 100 × 109/L 
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 (MPV) 
Serum B12 and folate 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
Helicopbacter pylori urea breath test (or another test per Investigator judgement) 
Serology for: 
HBV, HCV, HIV (if not done for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
Note: 
The above labs may change as additional data is assessed, and sites will be updated regarding any changes. 
 
8.5.4. 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding (MB) or 
clinically relevant, non-major bleeding events which are defined in Section 8.6.3, for example 
excess bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event 
occurs, additional testing of coagulation parameters (aPTT, PT, INR) and platelet count should 
be performed. 
8.5.5. 
Safety Monitoring Rules for Ocular Effects 
An ocular questionnaire designed to screen for vitamin A deficiency will be administered 
periodically (every 2 to 3 months) during Treatment Period.  Any patient who presents with new 
and persistent ocular symptoms compatible with vitamin A deficiency (e.g., night blindness or 
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dry eyes) should be referred for an ophthalmology examination.  If the ophthalmologist confirms 
the patient’s symptoms are consistent with vitamin A deficiency and/or the examination reveals 
physical findings that are consistent with vitamin A deficiency (but do not reach the stopping 
rule criteria described in Section 8.6.4) then additional work up with a corneal specialist should 
be considered.  In addition, it is suggested that a review of diet and supplement use and an 
evaluation for factors which may contribute to low vitamin A levels such as infection, alcohol 
consumption, and zinc and/or iron deficiency be conducted. 
Dosing with ION-682884 or inotersen may continue while these evaluations are being 
performed. 
8.6. 
Stopping Rules  
For the purposes of the stopping rules, Baseline is defined as:  average of the pre-dose test 
closest to Day 1 and Day 1.  
8.6.1. 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with ION-682884 or inotersen will be stopped permanently; values that are not confirmed due 
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 2 × Baseline value 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 2 × Baseline value if the Baseline value was > ULN) with 
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 and Temporary Stopping Rules 
for Renal Function Test Results 
Dosing should be stopped temporarily in the event of a persistent elevation that is observed over 
2 consecutive weeks, for any of the 4 criteria below: 
1. A decrease in eGFRcreat-cys > 50% (eGFRcreat-cys is calculated using the CKD-EPI 
creatinine-cystatin C equation [2012]).   
2. eGFRcreat-cys < 45 mL/min/1.73 m2 (if Baseline eGFRcreat-cys > 60 mL/min/1.73 m2) 
3. eGFRcreat-cys < 30 mL/min/1.73 m2 (if Baseline eGFRcreat-cys ≤ 60 mL/min/1.73 m2) 
4. Proteinuria:  Random UPCR > 5× Baseline AND > 1500 mg/g; or absolute UPCR 
value ≥ 2000 mg/g (confirmed by a repeat random spot UPCR ≥ 2000 mg/g or a 
24 hr UPCR ≥ 2000 mg/24 hr) 
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The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
If a dose is held, once eGFRcreat-cys increases to ≥ 45 mL/minute/1.73 m2, UPCR decreases to 
below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, dosing 
may be reinitiated.  In the case of UPCR of 2000 mg/g or higher, further evaluation for renal 
disease should be performed.  If acute glomerulonephritis is confirmed, treatment should be 
permanently discontinued.  
Dosing of a patient will be stopped permanently if urinalysis or renal blood tests confirm any of 
the following values in the absence of an alternative explanation agreed by a consulting 
nephrologist: 
• urine protein is > 2 g (in 24-hour urine) 
• creatinine clearance < 45 mL/min/1.73 m2 (if Baseline CKD-EPI > 60 mL/min/1.73 m2) 
• creatinine clearance < 30 mL/min/1.73 m2 (if Baseline CKD-EPI ≤ 60 mL/min/1.73 m2) 
Irrespective of whether the stopping rule is confirmed or not, the follow-up schedule and 
frequency of renal function monitoring after the initial event will be determined by the Study 
Medical Monitor in consultation with the Investigator and a renal consult will be requested. 
8.6.3. 
Stopping Rule for Platelet Count Results 
Please refer also to Table 4. 
In the event of any platelet count less than 25 × 109/L, dosing of the patient with ION-682884 or 
inotersen will be stopped permanently.  Platelet count should be monitored daily until 
2 successive values above 25 × 109/L.  Then monitor twice weekly until 3 successive values 
above 75 × 109/L.  Then weekly monitoring until 3 successive values ≥100 × 109/L.  
Administration of steroids is recommended for patients whose platelet count is less than 
50 × 109/L.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) 
recommend dexamethasone 40 mg daily for 4 days every 2–4 weeks for 1-4 cycles; 
prednis(ol)one 0.5-2 mg/kg/d for 2–4 weeks then taper; or methylprednisolone 30 mg/kg/day for 
7 days.  (Note:  Patient may require continuation with oral steroids after methylprednisolone.) 
In the event of a platelet count ˂ 75 × 109/L and ≥ 25 × 109/L, and in the absence of major 
bleeding (MB) or clinically relevant non-major bleeding (defined below), dosing with ION-
682884 or inotersen should be suspended temporarily until the platelet count has recovered to 
≥ 100 × 109/L.  The suitability of the patient for continued dosing will be determined by the 
Investigator in consultation with the Study Medical Monitor and will be based on factors such as 
the original rate of decline in the patient’s platelet count, whether any bleeding events were 
experienced, and the speed of recovery of platelet count after interruption of dosing.  Treatment 
should be held if there is no evaluable platelet count within 14 days ±7 days prior to the 
scheduled dose.  Any unreportable platelet count result must be rechecked and determined not to 
have met a stopping rule before dosing can continue.  
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Definition of Major Bleeding Events (Schulman and Kearon 2005) 
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome 
3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed red blood cells or 
whole blood or a fall in hemoglobin of 2.0 mg/dL (1.24 mmol/L) or more within 24 hours 
Definition of Clinically Relevant Non-Major Bleeding Events 
Clinically relevant non-major bleeding (CRNMB) 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. 
Definition of Minor Bleeding Events 
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. 
 
 
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Table 4: 
Actions in Patients with Low Platelet Count  
If the subsequent test confirms the initial test result, then monitoring frequency and dosing 
should be adjusted as recommended in the table.  Platelet monitoring and other safety actions 
apply to both treatment arms (ION-682884 and inotersen) as indicated below. 
Platelet 
Count  
(× 109/L) 
Platelet Monitoring Frequency and Other 
Safety Actions 
Dosing 
≥ 125 
Once every 4 weeks in ION-682884 treated 
patients. 
Once every 2 weeks in inotersen-treated 
patients and for 8 weeks after the last dose. 
ION-682884: Every-4-weeks dosing should be 
continued.  
Inotersen: Weekly dosing should be continued 
≥ 100 to < 
125   
Once every 2 weeks in ION-682884 treated 
patients. 
Once every 2 weeks in inotersen-treated 
patients and for 8 weeks after the last dose. 
Continued dosing of ION-682884 every-4-weeks 
or inotersen weekly at Investigator’s discretion. 
≥ 75 to 
< 100 
Once every week.  
Additional lab testing maybe performed per 
Section 8.5.3. 
For both treatment arms:  dosing should be 
paused until 3 successive values ≥ 100 × 109/L; 
on re-initiation of treatment, dosing frequency 
can be reduced per Investigator judgment in 
discussion with the Medical Monitor. 
≥ 50 to < 75 Twice weekly until 3 successive values 
above 75 × 109/L then weekly monitoring.   
Additional lab testing maybe performed per 
Section 8.5.3. 
Seek expert hematology consultation. 
For both treatment arms:  dosing should be 
paused until 3 successive values > 100 × 109/L; 
on re-initiation of treatment, dosing frequency 
can be reduced per Investigator judgment in 
discussion with the Medical Monitor. 
≥ 25 to 
< 50* 
Twice weekly until 3 successive values 
above 75 × 109/L; then weekly monitoring 
until ≥.100 x 109/L then per Schedule of 
Procedures.   
Consider more frequent monitoring if 
additional risk factors for bleeding are 
present‡. 
Seek expert hematology consultation 
Corticosteroids should be considered. 
Consider discontinuation of any antiplatelet 
agents or anticoagulants. 
Additional lab testing maybe performed per 
Section 8.5.3. 
Note:  if a patient’s platelet count falls to 
< 50 × 109/L, the Investigator must 
communicate to the Sponsor within 
24 hours of receiving the platelet result 
For both treatment arms:  dosing should be 
paused until 3 successive values > 100 × 109/L; 
on reinitiation of treatment dose should be 
reduced per Investigator judgment in discussion 
with the Medical Monitor. 
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Table 4: 
Actions in Patients with Low Platelet Count (Continued) 
Platelet 
Count  
(× 109/L) 
Platelet Monitoring Frequency and Other 
Safety Actions 
Dosing 
< 25* 
Daily until 2 successive values above 
25 × 109/L.  Then monitor twice weekly 
until 3 successive values above 75 × 109/L.  
Then weekly monitoring until stable. 
Seek expert hematology consultation 
Corticosteroids strongly recommended. 
Consider discontinuation of any antiplatelet 
agents or anticoagulants. 
Additional lab testing maybe performed per 
Section 8.5.3. 
Note:  if a patient’s platelet count falls to 
< 50 × 109/L, the Investigator must 
communicate to the Sponsor within 
24 hours of receiving the platelet result 
For both treatment arms:  treatment should be 
permanently discontinued.   
‡  Additional risk factors for bleeding include age > 60 years, receiving anticoagulant or antiplatelet medicinal 
products, and /or prior history of MB events 
* 
It is strongly recommended that, unless corticosteroids are contraindicated, the patient receives glucocorticoid 
therapy to reverse the platelet decline as recovery in platelet count may be accelerated by administration of 
high-dose steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
dexamethasone 40 mg daily for 4 days every 2–4 weeks for 1–4 cycles; prednis(ol)one 0.5–2 mg/kg/d for 
2-4 weeks then taper; or methylprednisolone 30 mg/kg/day for 7 days (note:  may require continuation with oral 
steroids after methylprednisolone) 
8.6.4. 
Stopping Rule for Ocular Effects 
A patient should be permanently discontinued from Study Drug administration if they 
demonstrate clear signs of vitamin A deficiency confirmed by an ophthalmologist and discussed 
with the Investigator. 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
No dose adjustment is planned, other than for safety reasons.  Any proposed adjustment to 
treatment schedule or dose level must be discussed with the Study Medical Monitor prior to 
initiation.  If the patient remains stable after adjustment, he/she may be cautiously returned to the 
original dose/regimen after consultation with the Study Medical Monitor. 
Patients may be dose paused in response to AEs ideally after consultation with the 
Study Medical Monitor.  Minimally, Study Medical Monitor should be notified of all dosing 
changes.  
8.8. 
Discontinuation of ION-682884 or Inotersen Treatment 
The reasons for permanently discontinuation of Study Drug administration are: 
• Patient request (no consent withdrawal for study participation) 
• Patient withdrawal of consent for study participation 
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• Protocol specific requirements 
O The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
O The patient presents laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1 to  8.6.4 
O The patient receives major organ transplantation 
• Investigator decision (e.g., AE, non-compliant patient) 
• Sponsor decision 
The reason for discontinuation of ION-682884 or inotersen must be recorded in the electronic 
Case Report Form (eCRF) and source documentation.   
The Investigator will also work with patients and Sponsor to determine followup study visits and 
assessments after treatment termination.  Ideally, patients who discontinue ION-682884 or 
inotersen treatment early will be encouraged to remain in the study and continue with protocol 
procedures and visits to collect efficacy endpoints and safety data.  This is especially important 
for efficacy assessment on the landmark visits (Weeks 35, 66, 85, and 105).  
Listed below is a guideline that can be used to determine which procedures should be performed 
depending on the patient’s willingness for follow-up.  Note that this will not account for all 
patient scenarios.  Investigators are encouraged to contact the Medical Monitor to discuss each 
patient that will discontinue study treatment early.  Variables such as length of time off drug, 
recent or current AEs including events described in Section 8.5 may result in modifications to the 
guidelines below. 
1. Patient agrees to full follow-up 
• Complete the Early Termination Visit  
• Complete any required safety monitoring (see Sections 8.5 and 9.4) 
• Ensure patient has 20 weeks of safety follow-up after the last dose of ION-682884 or 
inotersen 
• Complete of all remaining study visits and procedures through Week 85 as well as 
survival status at Week 105 
• Update AE and Concomitant Medication information through last contact 
2. Patient only agrees to targeted follow-up 
• Complete the Early Termination Visit  
• Complete any required safety monitoring (see Sections 8.5 and 9.4) 
• Return to the clinic to complete key efficacy assessments (serum TTR reduction, 
mNIS+7, Norfolk QOL-DN) on the landmark visits (Weeks 35, 66, 85, and 105) 
• Ensure patient has 20 weeks of safety follow-up after the last dose of ION-682884 or 
inotersen 
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• Update AE and Concomitant Medication information through last contact 
3. Patient only agrees to survival status follow-up 
• Request that patient complete the Early Termination Visit  
• Request completion of any required safety monitoring (see Sections 8.5 and 9.4) 
• Collect data (e.g., AEs, concomitant medications, survival status) at Weeks 35, 
66, 85, and 105 from one or more sources agreed to by patient (i.e., via 
correspondence/communication with patient, family/friends, other physicians, and/or 
from review of the medical records, as allowed per local laws and as stated in the 
IEC/IRB-approved ICF) 
8.9. 
Discontinuation of Study Participation 
The reasons for discontinuing patient participation in the study are: 
• Patient withdrawal of consent for study participation 
• At the discretion of the Investigator or Sponsor for noncompliance or significant 
protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  Reason for withdrawal from study must be recorded in the eCRF.  
If consent is withdrawn, patient will be removed from further treatment and study observation 
immediately upon the date of request.   
Withdrawal of consent by patient should be avoided as much as possible so that patient can be 
followed up in the trial for safety and efficacy.  Ideally, attempts need to be made to complete 
landmark visits.  Minimally, communication should be established with patients to obtain vital 
status at Weeks 35, 66, 85, and 105 by using the type of follow-up the patient is agreeable to: in 
person, by phone/mail, through family/friends, via correspondence/communication with other 
physicians, and/or from review of the medical records.  The agreed means of follow-up will be 
documented in the patient records and notified to the Sponsor.   
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. 
8.10.1. 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
of informed consent and the last study visit.  
Patients are required to take daily RDA supplemental doses of vitamin A during the Treatment 
and Post-Treatment Evaluation Periods.  The vitamin A supplements will be provided by the 
Study Center and/or Sponsor.  A patient may be allowed to substitute the Study Center provided 
vitamin A supplement with their own, only after consultation with the Study Medical Monitor.  
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Additional vitamin A supplements (other than those described above) are not allowed at any time 
during the study unless approved by the Study Medical Monitor (this includes multivitamin 
supplements that contain vitamin A). 
Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
Concomitant therapy with the following drugs is not allowed:  Vyndaqel® / Vyndamax™ 
(tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran) or off-label use of diflunisal.  
Doxycycline short term use for the indication of infection (< 15 days) is allowed.  
8.10.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and the last study visit.  
8.11. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded in the eCRF by Study Center 
staff.   
Patients will record treatment in a dosing diary that will be reviewed periodically by Study 
Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1. 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor in accordance with 
the applicable Ionis and/or designee SOPs throughout the conduct of the clinical trial. 
9.2. 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of SAEs 
including suspected unexpected serious adverse reactions (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 (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  The DSMB will be notified of any SAE as specified in 
the DSMB charter. 
In addition to the Investigator’s assessment of relatedness, the Sponsor will evaluate the 
available information and perform an independent assessment of all reported SAEs and 
determine if there is a reasonable possibility that the ION-682884 or inotersen is causally related 
to a reported SAE.  While the Sponsor may upgrade an Investigator’s decision it is not 
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permissible to downgrade the Investigator’s opinion for the purposes of determining whether the 
SAE meets the definition of a SUSAR.  If the event is considered by the Sponsor or designee to 
meet the definition of a SUSAR, the event will be reported. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population.   
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An 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 or inotersen 
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 adverse drug reactions. 
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. 
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. 
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A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
9.3.3. 
Serious Adverse Event (SAE) 
A SAE is any 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 adverse reaction that, had it occurred 
in a more severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as an admission of greater than 24 hours to a medical 
facility and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Results in a congenital anomaly or birth defect in the offspring of the patient (whether 
the patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse 
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  
Adverse events 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 could be appropriate. 
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Adverse events of special interest, if defined in the study protocol, are required to be reported by 
the Investigator to the Sponsor immediately, no more than 24 hours of the Investigator’s first 
knowledge of the event. 
For the purpose of this study, severe reductions in platelet count < 50 × 109/L accompanied by a 
MB or CRNMB, or platelet count of < 25 × 109/L independent of a MB or CRNMB event are 
considered as AEs of special interest and should be subject to 15-day expedited reporting by the 
Sponsor to the regulatory agencies. 
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 subject safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to ION-682884 or inotersen) should be reported to the Sponsor 
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 subject’s 
Follow-up Period which is defined as the final study visit (Week 105 or last visit if patient early 
terminates).  SAEs should be reported using an electronic SAE submission form within 
Electronic Data Capture (EDC) whenever possible.  In situations where the electronic SAE 
submission via EDC is unavailable, an Initial Serious Adverse Event Form should be completed 
and a copy should be faxed or emailed to the Sponsor.  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 Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2. 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s Follow-up Period, which is defined as the final study visit 
(Week 105 or last visit if patient early terminates; Section 3.4.3).  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 use of ION-682884 or Inotersen 
The event’s relationship to ION‑682884 or inotersen is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of ION-682884 or 
inotersen, 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 ION‑682884 or inotersen 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 ION‑682884 or inotersen 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 ION-682884 or inotersen 
9.4.3.2. 
Severity 
The severity of AEs and SAEs relating to laboratory tests and AEs at the injection site 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 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.2). 
9.4.3.3. 
Action Taken with ION-682884 / Inotersen 
Action taken with ION‑682884 or inotersen due to the event is characterized by 1 of the 
following. 
• None:  No changes were made to treatment and dosing 
• Permanently Discontinued:  Treatment 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 
• Reduced schedule:  Dosing frequency was reduced 
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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 a non-serious AE on the 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) 
9.4.3.6. 
Follow-up of Adverse Event 
Investigator Follow-Up 
During the Study Period, the Investigator should follow each AE until the event has resolved to 
Baseline grade or better, the event is assessed as stable, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all SAEs considered to be 
related to ION-682884 or inotersen, or related to study procedures until a final outcome can be 
reported. 
Resolution of AE (with dates) should be documented on the Adverse Event eCRF and in the 
patient’s medical record to facilitate source data verification.  
Investigator should follow-up, or support the Sponsor’s effort to follow up with all pregnancies 
reported during the study from either the study patient or the female partner of male study patient 
until pregnancy outcome is available.  
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Sponsor Follow-Up 
For SAEs, AESI and pregnancy cases in patients who have completed or terminated study, the 
Sponsor or a designee should follow-up by telephone, fax, email, and/or a monitoring visit 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. 
9.5. 
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. 
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 
ION‑682884 or inotersen errors (including overdose, underdose, and administration error) should 
be documented as Protocol Deviations, subcategory Dosing Error.  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. 
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Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of ION‑682884 or inotersen 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.  Any overdose or incorrect administration of ION-682884 or inotersen 
should be noted on the Study Drug Administration eCRF.  All AEs associated with an overdose 
or incorrect administration of ION-682884 or inotersen 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 refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4. 
Contraception and Pregnancy 
Male patients and female patients of child-bearing potential must continue to use appropriate 
highly effective 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 within 
24 hours of first learning of the occurrence of pregnancy.  Follow-up information including 
delivery or termination is reported by designating as ‘Follow-up’ on the Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility.   
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with ION-682884 or inotersen.  However, the patient will be 
encouraged to complete the post-treatment follow-up portion of the study to the extent that study 
procedures do not interfere with the pregnancy.  Regardless of continued study participation, the 
study physician will assist the patient in getting obstetrical care and the progress of the 
pregnancy will be followed until the outcome of the pregnancy is known (i.e., delivery, elective 
termination, or spontaneous abortion).  If the pregnancy results in the birth of a child, the Study 
Center and Sponsor may require access to the mother and infant’s medical records to obtain 
additional information relevant to the pregnancy progress and outcome.  A longer follow-up may 
be required if a 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 
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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 a 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. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Study Endpoints  
Study endpoints are described in Section 1.2. 
10.2. 
Sample Size Considerations 
The sample size for this study was estimated based on the data from the NEURO-TTR clinical 
trial.  
With 140 patients (120 of them dosed with ION-682884) and assuming a 10% dropout rate, there 
would be 108 evaluable patients treated with ION-682884.  In the NEURO-TTR trial, there are 
52 evaluable placebo patients.  
It is observed that the NEURO-TTR placebo group had a 23.8 point increase in the mNIS+7 
score from Baseline to Week 66.  It is estimated that the ION-682884 group will have a 4.2 point 
increase in mNIS+7.  The standard deviation of the change from Baseline is estimated to be 20.  
There would be at least 90% power to detect a 19.6 point difference in the change from Baseline 
of the mNIS+7 score between ION-682884-treated patients and the NEURO-TTR-placebo 
patients, with a 2-sided alpha level of 0.025.  
For the Norfolk QOL-DN, it is observed that the NEURO-TTR placebo group had 10.7 points 
change from Baseline to Week 66.  It is estimated that the ION-682884-treated group will have a 
0 point change from Baseline.  The standard deviation is estimated to be 20.  There would be at 
least 80% power to detect a 10.7 points difference in the change from Baseline of the Norfolk 
QOL-DN between ION-682884-treated patients and the NEURO-TTR placebo patients, with a 
2-sided alpha level of 0.025.  
For the TTR percent change from Baseline, it is observed that the NEURO-TTR placebo group 
had 9.7% reduction from Baseline to Week 65.  It is estimated that the ION-682884-treated 
group will have at least 80% reduction from Baseline.  The standard deviation is estimated to be 
13%.  There would be at least 95% power to detect a 70.3% difference in the percent change 
from Baseline between ION-682884-treated patients and the NEURO-TTR-placebo patients, 
with a 2-sided alpha level of 0.025.  
10.3. 
Populations 
The population definitions that will be used in this study are provided below and are very similar 
to those employed in the NEURO-TTR trial.   
Full Analysis Set:  All randomized patients who received at least 1 injection of ION-682884 or 
inotersen and who have a Baseline and at least 1 post-Baseline efficacy assessment for mNIS+7 
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score or Norfolk QOL-DN questionnaire total score.  For NEURO-TTR trial, the Full Analysis 
Set includes all randomized patients who received at least 1 injection of Study Drug (inotersen or 
placebo) and who have a Baseline and at least 1 post-Baseline efficacy assessment for the 
mNIS+7 score or Norfolk QOL-DN questionnaire total score. 
Per Protocol Set:  A subset of Full Analysis Set who received at least a certain percentage of the 
prescribed doses of ION‑682884 and that have no significant protocol deviations that would be 
expected to affect efficacy assessments.  The detailed criteria will be specified in the SAP.  For 
NEURO-TTR trial, the Per-Protocol Set includes the subset of the NEURO-TTR Full Analysis 
Set who have received at least 80% of the prescribed doses of Study Drug (inotersen or placebo) 
and who have no major protocol violations that would be expected to affect efficacy 
assessments.   
Safety Set:  All patients who are randomized and receive at least 1 dose of ION-682884 or 
inotersen.  For NEURO-TTR trial, the Safety Set includes all randomized patients who received 
at least 1 injection of Study Drug (inotersen or placebo). 
PK Population:  All patients who are randomized and receive at least 1 dose of ION-682884 or 
inotersen and have at least 1 evaluable PK sample. 
10.4. 
Definition of Baseline 
The same Baseline definitions from the NEURO-TTR trial will be applied in this study.  The 
Baseline for efficacy, PD and safety assessments will be defined as follows: 
• Baseline mNIS+7 and its individual components will be defined as the average of 
2 assessments taken within 60 days prior to the first dose of ION-682884 or inotersen.  
If only one assessment has been done, the single assessment will be used in place of the 
average.  Rarely, for patient convenience, the Baseline mNIS+7 assessment(s) (or a 
subset of this assessment) will have been completed early in the Treatment Period rather 
than pre-treatment.  These will be considered protocol deviations.  These assessments 
will be included in the analysis as valid Baseline assessments provided they are taken 
within 1 week after the first dose.  The rationale for this is that the pharmacology of the 
drug indicates that the drug will have no effect on mNIS+7 this early in treatment, and 
including these values as the Baseline assessments will allow these patient’s data to be 
included in the primary analysis.   
• Baseline NSC and individual components will be defined as the average of 2 assessments 
taken within 60 days prior to the first dose of ION-682884 or inotersen.  If only 
1 assessment has been done, the single assessment will be used in place of the average.  
Because NSC score is collected during the NIS assessment procedure, it is possible it 
could be completed early in the Treatment Period rather than pre-treatment.  These will 
be considered protocol deviations.  These assessments will be included in the analysis as 
valid Baseline assessments, provided they are taken within 1 week after the first dose. 
• Baseline ECG will be defined as the average of the triplicate taken on Day 1 pre-dose.  
If only 1 or 2 assessments are available, the single assessment or average of the 
2 assessments will be used.  If the case that Day 1 pre-dose ECG is missing, screening 
visit results will be used as Baseline.  
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• Baseline laboratory assessment including PD will be defined as the average of all 
non-missing pre-dose assessments.  
Baseline for all other assessments will be defined as the last non-missing value prior to the first 
dose of study drug (ION-682884 or inotersen).  
10.5. 
Interim Analysis and Multiplicity 
An interim analysis will be performed to assess the efficacy and safety profile of ION-682884 
comparing to the placebo arm of Neuro-TTR when all patients on ION-682884 complete 
Week 35 assessments.  
Week 35 Interim Analysis  
The multiplicity will be controlled by using the ranking strategy in the following testing 
sequence:  
• Interim Analysis PEP.  Comparison of percent change from Baseline to Week 35 in the 
TTR between ION-682884 and NEURO-TTR placebo in the Full Analysis Set. 
• Interim Analysis PEP.  Comparison of change from Baseline to Week 35 in the mNIS+7 
between ION-682884 and NEURO-TTR placebo in the Full Analysis Set. 
• Interim Analysis Secondary Endpoint.  Comparison of change from Baseline to Week 35 
in the Norfolk total score between ION-682884 and NEURO-TTR placebo in the Full 
Analysis Set.   
The statistical analysis will be conducted with 2-sided alpha level of 0.025.  If any of the 
endpoint is not statistically significant, the remaining test(s) will not be conducted in the interim 
analysis. 
Week 66 Final Analysis 
The multiplicity for the final analysis will be controlled by using the ranking strategy in the 
following testing sequence:  
• Co-Primary Endpoint:  Comparison of percent change from Baseline to Week 65 in the 
TTR between ION-682884 and NEURO-TTR placebo in the Full Analysis Set   
• Co-Primary Endpoint:  Comparison of change from Baseline to Week 66 in the mNIS+7 
between ION-682884 and NEURO-TTR placebo in the Full Analysis Set   
• Co-Primary Endpoint:  Comparison of change from Baseline to Week 66 in the Norfolk 
total score between ION-682884 and NEURO-TTR placebo in the Full Analysis Set 
• Secondary Endpoint:  Comparison of change from Baseline to Week 66 in the NSC 
between ION-682884 and NEURO-TTR placebo in the Full Analysis Set 
• Secondary Endpoint:  Comparison of change from Baseline to Week 35 in the NSC 
between ION-682884 and NEURO-TTR placebo in the Full Analysis Set  
• Secondary Endpoint:  Comparison of change from Baseline in the PCS score of SF-36 at 
Week 65 between ION-682884 or NEURO-TTR placebo in the Full Analysis Set  
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• Secondary Endpoint:  Comparison of change from Baseline to Week 65 in the PND 
between ION-682884 and NEURO-TTR placebo in the Full Analysis Set 
• Week 66 Final Analysis Secondary Endpoint:  Comparison of change from Baseline to 
Week 65 in mBMI between ION-682884 and NEURO-TTR placebo in the Full Analysis 
Set  
In the Week 66 Final Analysis, for those statistically significant endpoints at Week 35 Interim 
Analysis, their corresponding tests at the Week 66 Final Analysis will not be conducted in the 
ranking strategy for multiplicity.  The first test will be for the endpoint which is not statistically 
significant at the Week 35 Interim Analysis.  The alpha level for this endpoint will be determined 
by the resampling procedure (Westfall and Young 1993) as follows. 
Let T1 and T2 be the standardized test statistics at the interim and final analyses, respectively.  In 
order to determine the alpha level for the final analysis, the correlation between T1 and T2 is first 
estimated based on the resampling approach:  
• Among the 108 ION-682884 treated patients and 52 NEURO-TTR placebo patients, 
randomly assign 108 patients to the ION-682884 treated group and 52 patients to 
NEURO-TTR placebo group 
• Apply the re-randomized treatment assignment to the interim data and obtain the 
standardized test statistics T1  
• Apply the re-randomized treatment assignment to the final data and obtain the 
standardized test statistics T2  
Repeat the above procedure N times (N = 10000) and obtain N pairs of test statistics T1 and T2.  
The correlation between T1 and T2 will then be estimated as the sample correlation of the 
N pairs.  
Let c1 be the cut-off point for the interim 2-sided test corresponding to an alpha of 0.025.  Once 
the estimated correlation ρ is available, the cut-off point c2 for the final analysis is obtained by 
solving the nonlinear equation Pr(|T1| ≥ c1 or |T2| ≥ c2) = 0.05, where (T1, T2) follow a bivariate 
normal distribution with mean vector (0, 0), standard deviations of 1 and correlation ρ.  
For those endpoints that are not tested in the interim analysis, significant level of 0.05 will be 
used in the final analysis. 
10.6. 
Planned Methods of Analysis 
All eCRF data, lab data transfers, mNIS+7 score data, as well as any outcomes derived from the 
data, will be provided in the patient data listings.  Patient data listings will be presented for all 
patients enrolled into the study.   
Descriptive summary statistics including n, mean, median, standard deviation, interquartile range 
(25th percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and 
counts and percentages for categorical variables will be used to summarize most data by 
treatment group.  Where appropriate, p-values will be reported.  All statistical tests will be 
conducted using 2-sided tests with 5% Type I error rates unless otherwise stated.  
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All primary, secondary and PD endpoints will be assessed on the Full Analysis Set and 
Per-Protocol Set, with the former being the basis for the primary efficacy analysis.  All safety 
assessments will be performed on the Safety Set.  PK endpoints will be assessed in the PK Set as 
applicable.  
The reference arm (inotersen) will be summarized descriptively and no statistical comparison 
will be made between the reference arm and the ION-682884-treated arm.  
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2. 
Efficacy Analysis  
10.6.2.1. Primary Analysis 
10.6.2.1.1. Primary Analysis at Interim Analysis 
Below are the 2 primary analyses for interim analysis  
• Comparison of percent change from Baseline to Week 35 in the TTR between 
ION-682884 and NEURO-TTR placebo in the Full Analysis Set 
• Comparison of change from Baseline to Week 35 in the mNIS+7 between 
ION-682884 and NEURO-TTR placebo in the Full Analysis Set 
The percent change in TTR from Baseline to Week 35 will be analyzed using the Mixed Effects 
Model with Repeated Measures (MMRM) model adjusted by propensity score weights.  The 
MMRM model will also include the effects of treatment (ION-682884 or NEURO-TTR 
placebo), time (categorical), disease stage (Stage 1/Stage 2), V30M mutation (Yes/No), previous 
treatment (Yes/No), treatment-by-time interaction, baseline value of the endpoint, and the 
baseline-by-time interaction.  The propensity score will be calculated for each NEURO-TTR 
placebo or ION-682884 patient using a logistic regression model with Baseline covariates 
including disease stage (Stage 1/Stage 2), V30M mutation (Yes/No), and previous treatment 
(Yes/No).  
The second PEP mNIS+7 is scheduled to be assessed at Week 35, Week 66, and Week 85.  
Because only 1 post-Baseline assessment (Week 35) is available at Week 35 Interim Analysis, 
the treatment comparison at Week 35 will be based on the analysis of covariance (ANCOVA) 
model adjusted by propensity score.  The ANCOVA model will also include the effects of 
treatment (ION-682884 or NEURO-TTR placebo), disease stage (Stage 1/Stage 2), V30M 
mutation (Yes/No), previous treatment (Yes/No), and the Baseline value of the endpoint.  
Patients with a missing mNIS+7 at Week 35 will have value multiply imputed using an 
imputation model that contains the following variables:  disease stage (Stage 1/Stage 2), V30M 
mutation (Yes/No), previous treatment (Yes/No), and the Baseline value of the endpoint and the 
multiple imputation will be stratified by treatment group (Schafer 1997; Schafer 1999).  Any 
patient who discontinues early from the Treatment Period will be strongly encouraged to 
complete landmark assessments. 
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10.6.2.1.2. Primary Analysis at Week 66 Final Analysis 
For percent change from Baseline of TTR at Week 65, change from Baseline of mNIS+7 at 
Week 66, and change from Baseline of Norfolk QOL-DN at Week 66, MMRM model adjusted 
by propensity score weights will be used.   
10.6.2.2. Secondary Analysis 
10.6.2.2.1. Secondary Analysis at Interim Analysis 
The secondary analysis at interim analysis is the comparison of change from Baseline to 
Week 35 in the Norfolk total score between ION-682884 and NEURO-TTR placebo in the 
Full Analysis Set.  The analysis will be conducted in the same way as for the mNIS+7 in the 
Week 35 Interim Analysis.  
10.6.2.2.2. Secondary Analysis at Final Analysis 
The secondary endpoints at Week 66 Final Analysis include the following analyses:   
• Comparison of change from Baseline to Week 66 in the NSC between ION-682884 
and NEURO-TTR placebo in the Full Analysis Set 
• Comparison of change from Baseline to Week 35 in the NSC between ION-682884 
and NEURO-TTR placebo in the Full Analysis Set  
• Comparison of change from Baseline in the PCS score of SF-36 at Week 65 between 
ION-682884 or NEURO-TTR placebo in the Full Analysis Set  
• Comparison of change from Baseline to Week 65 in the PND between ION-682884 
and NEURO-TTR placebo in the Full Analysis Set.  
• Comparison of change from Baseline to Week 65 in mBMI between ION-682884 and 
NEURO-TTR placebo in the Full Analysis Set  
The secondary analyses will be conducted in the same way as for the primary analysis at 
Week 66 Final Analysis.  
10.6.2.3. Pharmacodynamic Analysis  
Pharmacodynamic analyses include comparisons of change from Baseline in TTR between 
ION-682884 and NEURO-TTR placebo group.  The data will be analyzed in the same way as for 
the PEP at Week 66 Final Analysis. 
10.6.2.4. Exploratory Analyses 
Exploratory analysis includes the comparisons of change from Baseline in ECHO parameters, at 
Week 66 and NT-proBNP at Week 65 between ION-682884 or the NEURO-TTR placebo group.  
Additional analyses on the all cause hospitalizations in all patients at Week 66, all cause 
hospitalizations in patients with cardiac involvement at Week 66, mNIS+7 and Norfolk 
QOL-DN at Week 85, 10MWT, R-ODS, COMPASS-31 and EQ-5D-5L at Weeks 37 and 81 will 
be provided.  PGIS and PGIC will be assessed for purposes of psychometric analyses of selected 
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clinical outcome assessment measures. Details of exploratory analyses will be provided in the 
SAP. 
10.6.3. 
Pharmacokinetic and Immunogenicity Analysis 
10.6.3.1. Pharmacokinetic Analysis 
Noncompartmental PK analysis of ION-682884 (as total full-length oligonucleotides, including 
fully, partially, and un-conjugated ION-682884) or inotersen will be carried out on each 
individual patient data set in the PK subgroup where limited intensive plasma PK samples are 
collected following the dose on Days 1, 225, and 449.  The maximum observed drug 
concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  Partial areas under the plasma concentration time- curve from time zero 
(pre-dose) to the last observable concentration (AUC0-t) after SC administration will be 
calculated using the linear-up logdown- trapezoidal method.   
For all evaluable patients receiving ION-682884 or inotersen, plasma drug concentrations during 
the Treatment Period and at the Post-Treatment Follow-Up Period will be listed by treatment, 
dose, study day, time point, patient ID, patient anti-drug antibody (ADA) status, and summarized 
using descriptive statistics, with and without stratification by patient immunogenicity status.  The 
apparent plasma terminal elimination half-life of ION-682884 or inotersen following the last 
administered dose will be calculated in each evaluable patient with post-treatment PK samples 
collected (when deemed possible by the PK scientist). 
Plasma PK parameters will be summarized using descriptive statistics, with and without 
stratification by patient immunogenicity status.  Other PK parameters, as appropriate, may be 
determined or calculated at the discretion of the PK scientist.  Additional details regarding the 
PK analysis will be described in the SAP. 
Potential relationships between selected PD and plasma exposure measures (e.g., trough 
concentrations) may also be explored, where deemed appropriate. 
10.6.3.2. Immunogenicity Analysis 
ADA will be determined in a multi-tiered approach that includes screening, confirmation, and 
titration (if confirmed positive) assays at Baseline, during treatment, and at the end of Follow-Up 
Period for all patients (receiving either ION-682884 or inotersen) in the study.  Immunogenicity 
results (screen positive/negative, confirmed positive/negative or not evaluable, and when 
applicable, titer of ADA) before, during, and after treatment with ION-682884 or inotersen 
(i.e., sample ADA status) will be listed.  Patient ADA status (positive/negative or not evaluable) 
for all evaluable patients, along with the study day that the first positive immunogenicity status 
emerged (Tfirst, i.e., onset of ADA development), the last positive immunogenicity status 
observed (Tlast), the last ADA sample collection day, and peak titer if applicable, will be listed by 
their treatment and study day.  Patients with positive ADA status may be further classified 
(where applicable) as being either ‘persistent’, ‘transient’, or ‘not determinable’, if deemed 
appropriate. 
Additionally, the sample and patient immunogenicity incidence (number) and incidence rate 
(percent) will be summarized as the total number and percent of evaluated patients with antibody 
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negative, positive, and unknown status by treatment and dose.  Furthermore, onset, titer over 
time, and peak titer of the ADA response, if applicable, will be summarized as median, quartiles 
(25% and 75%), and range by treatment and dose. 
Potential effect of immunogenicity on efficacy and safety will be evaluated.  Additional details 
regarding the IM data analysis will be described in the SAP. 
10.6.4. 
Safety Analysis 
Treatment duration and amount of ION-682884 or inotersen received will be summarized by 
treatment group, as well as reasons for any withdrawals from ION-682884 or inotersen. 
All treatment-emergent adverse events (AEs with onset after the first dose of ION-682884 or 
inotersen) and SAEs will be summarized for each treatment group using the MedDRA™ coding 
system, by system organ class, preferred term, relationship to ION-682884 or inotersen, and 
severity.  Narratives of deaths, SAEs, including early withdrawals from ION-682884 or inotersen 
and from study due to AEs, will also be provided. 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
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 ION-682884 or inotersen administration, as appropriate.  
Vital sign and ECG measures will be tabulated.  In addition, the number of patients who 
experience abnormalities in clinical laboratory evaluations will be summarized. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific screening 
procedures or any ION‑682884 or inotersen are administered.  The patient must be given 
sufficient time to consider whether to participate in the study.  The informed consent may be 
administered remotely using locally accepted methods. 
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient. 
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11.2. 
Ethical Conduct of the Study 
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 (IEC)/Institutional Review Board 
(IRB) 
A copy of the protocol, proposed informed consent form, other written patient information, 
and any proposed advertising material must be submitted to the IEC/IRB for written approval.  
A copy of the written approval of the protocol and informed consent form must be received by 
the Sponsor before recruitment of patients into the study and shipment of ION-682884 or 
inotersen.  A copy of the written approval of any other items/materials that must be approved by 
the Study Center or IEC/IRB must also be received by the Sponsor before recruitment of patients 
into the study and shipment of ION-682884 or inotersen.  The Investigator’s Brochure must be 
submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with 
ICH GCP.  The Investigator should also notify the IEC/IRB of SAEs occurring at the Study 
Center and other AE reports received from the Sponsor, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4. 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor, 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 (e.g., signed informed consent forms) should be kept in strict 
confidence by the Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IRB/IEC 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 
IRB/IEC to the Sponsor. 
12.2. 
Study Termination 
The Sponsor reserves the right to terminate the study.  The Investigator reserves the right to 
terminate their participation in the study, according to the terms of the site contract.  The 
Investigator should notify the IRB in writing of the trial’s completion or early termination and 
send a copy of the notification to the Sponsor. 
12.3. 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an 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.   
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 
ICH GCP, suitable for inspection at any time by representatives from the Sponsor 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 IRB/IEC 
and the Sponsor 
• If drug supplies are maintained at the Study Center, proof of receipt, ION-682884 or 
inotersen Product Accountability Record, Return of ION-682884 or inotersen Product 
for Destruction, final ION-682884 or inotersen 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. 
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No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., case report forms and other pertinent data) provided that 
patient confidentiality is respected. 
The Sponsor will be blinded for mNIS+7 and Norfolk-QOL-DN throughout the study, to 
decrease bias in the conduct of the study.  
The Sponsor monitor 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.  The access to these records may include 
viewing your medical records remotely, from a location outside of the study center (where 
allowed locally). 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing case report forms, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor.  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5. 
Language 
Case report forms must be completed in English.  Generic names and trade names are acceptable 
for concomitant medications.  Combination medications should be recorded using their trade 
name. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
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12.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 
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13. 
REFERENCES 
Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary 
Transthyretin Amyloidosis. N Engl J Med 2018; 379: 11-21. 
Adams D, Hawkins PN, and Polydefkis M. Oligonucleotide Drugs for Transthyretin Amyloidosis. N Engl 
J Med 2018; 379: 2086. 
Adams D, Lozeron P, and Lacroix C. Amyloid neuropathies. Curr Opin Neurol 2012; 25: 564-572. 
Adams D, Samuel D, Goulon-Goeau C, et al. The course and prognostic factors of familial amyloid 
polyneuropathy after liver transplantation. Brain 2000; 123 ( Pt 7): 1495-1504. 
Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of 
transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2016; 29 Suppl 1: S14-26. 
Benson MD, Dasgupta NR, Rissing SM, et al. Safety and efficacy of a TTR specific antisense 
oligonucleotide in patients with transthyretin amyloid cardiomyopathy. Amyloid 2017; 24: 217-223. 
Benson MD, Kluve-Beckerman B, Zeldenrust SR, et al. Targeted suppression of an amyloidogenic 
transthyretin with antisense oligonucleotides. Muscle Nerve 2006; 33: 609-618. 
Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen Treatment for Patients with Hereditary 
Transthyretin Amyloidosis. N Engl J Med 2018; 379: 22-31. 
Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a 
randomized clinical trial. Jama 2013; 310: 2658-2667. 
Biesalski HK, Frank J, Beck SC, et al. Biochemical but not clinical vitamin A deficiency results from 
mutations in the gene for retinol binding protein. Am J Clin Nutr 1999; 69: 931-936. 
Bui BV, Armitage JA, Fletcher EL, et al. Retinal anatomy and function of the transthyretin null mouse. 
Exp Eye Res 2001; 73: 651-659. 
Buxbaum JN Reixach N. Transthyretin: the servant of many masters. Cell Mol Life Sci 2009; 66: 3095-
3101. 
Castano A, Drachman BM, Judge D, et al. Natural history and therapy of TTR-cardiac amyloidosis: 
emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart 
Fail Rev 2015; 20: 163-178. 
Coelho T, Ericzon BG, Falk R, et al. A Physician’s Guide to Transthyretin Amyloidosis 2008:  
Coelho T, Ines M, Conceicao I, et al. Natural history and survival in stage 1 Val30Met transthyretin 
familial amyloid polyneuropathy. Neurology 2018; 91: e1999-e2009. 
Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid 
polyneuropathy: a randomized, controlled trial. Neurology 2012; 79: 785-792. 
Coutinho P, Martins da Silva A, Lopes Lima J, et al. Forty years of experience with Type 1 amyloid 
neuropathy. Review of 483 cases. Amyloid and Amyloidosis 1980: 88-98. 
D'Ambrosio DN, Clugston RD, and Blaner WS. Vitamin A metabolism: an update. Nutrients 2011; 3: 63-
103. 
Episkopou V, Maeda S, Nishiguchi S, et al. Disruption of the transthyretin gene results in mice with 
depressed levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci U S A 1993; 90: 2375-2379. 
Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation 2011; 124: 1079-1085. 
FDA Guidance for Industry Jp-. Guidance for industry: estimating the maximum safe starting dose in 
initial clinical trials for therapeutics in adult healthy volunteers. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078
932.pdf. 2005:  
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Fleming CE, Nunes AF, and Sousa MM. Transthyretin: more than meets the eye. Prog Neurobiol 2009; 
89: 266-276. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 
2'-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab 
Dispos 2003; 31: 1419-1428. 
Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care 
2017; 23: S107-S112. 
Herlenius G, Wilczek HE, Larsson M, et al. Ten years of international experience with liver 
transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic 
Polyneuropathy World Transplant Registry. Transplantation 2004; 77: 64-71. 
Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and 
cystatin C. N Engl J Med 2012; 367: 20-29. 
Kwoh J. 2008 Chapter 13: An Overview of the Clinical Safety Experience of First- and Second-
Generation Antisense Oligonucleotides. in S. T.  Crooke (ed.), Antisense Drug Technology: Principles, 
Strategies, and Applications (Boca Raton). 
Levin AA, Yu RZ, and Geary RS. 2008 Chapter 7: Basic Principles of the Pharmacokinetics of Antisense 
Oligonucleotide Drugs. in S. T.  Crooke (ed.), Antisense Drug Technology: Principles, Strategies, and 
Applications (CRC Press: Boca Raton). 
Liepnieks JJ Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin 
amyloidosis patients after liver transplantation. Amyloid 2007; 14: 277-282. 
Liepnieks JJ, Zhang LQ, and Benson MD. Progression of transthyretin amyloid neuropathy after liver 
transplantation. Neurology 2010; 75: 324-327. 
Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light chains and serum N-terminal 
natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. 
Blood 2006; 107: 3854-3858. 
Plante-Bordeneuve V Said G. Familial amyloid polyneuropathy. Lancet Neurol 2011; 10: 1086-1097. 
Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using 
triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 2014; 42: 
8796-8807. 
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and 
management of primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Quintas A, Vaz DC, Cardoso I, et al. Tetramer dissociation and monomer partial unfolding precedes 
protofibril formation in amyloidogenic transthyretin variants. J Biol Chem 2001; 276: 27207-27213. 
Schafer JL. Analysis of Incomplete Multivariate Data.  eBook 
http://www.ii.uni.wroc.pl/~bitro/wojtki/e_book/Analisis/4061fm.pdf. Chapman and Hall/CRC 1997:  
Schafer JL. Multiple imputation: a primer. Stat Methods Med Res 1999; 8: 3-15. 
Schmidt HH, Waddington-Cruz M, Botteman MF, et al. Estimating the global prevalence of transthyretin 
familial amyloid polyneuropathy. Muscle Nerve 2018; 57: 829-837. 
Schulman S Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal 
products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694. 
Seeliger MW, Biesalski HK, Wissinger B, et al. Phenotype in retinol deficiency due to a hereditary defect 
in retinol binding protein synthesis. Invest Ophthalmol Vis Sci 1999; 40: 3-11. 
Sekijima Y, Yoshida K, Tokuda T, et al. Familial Transthyretin Amyloidosis 2009:  
Sletten DM, Suarez GA, Low PA, et al. COMPASS 31: a refined and abbreviated Composite Autonomic 
Symptom Score. Mayo Clin Proc 2012; 87: 1196-1201. 
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Stangou AJ Hawkins PN. Liver transplantation in transthyretin-related familial amyloid polyneuropathy. 
Curr Opin Neurol 2004; 17: 615-620. 
Stewart M, Lenderking W, and Loftus J. Evaluating the quality of life and burden of illness in an ultra-
rare disease in the U.S.: transthyretin familial amyloid polyneuropathy (TTR-FAP) patients & caregivers. 
Abstract presented at: the IXth International Syposium on Familial Amyloidotic Polyneuropathy (ISFAP); 
November 10-13, 2013; Rio de Janeiro, Brazil. Abstract E16. 2013:  
Suhr O, Danielsson A, Rydh A, et al. Impact of gastrointestinal dysfunction on survival after liver 
transplantation for familial amyloidotic polyneuropathy. Dig Dis Sci 1996; 41: 1909-1914. 
The EuroQol Group. The EuroQol Group. EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy 1990.16(3): 199-208. 
van Nes SI, Vanhoutte EK, van Doorn PA, et al. Rasch-built Overall Disability Scale (R-ODS) for 
immune-mediated peripheral neuropathies. Neurology 2011; 76: 337-345. 
Vinik EJ, Vinik AI, Paulson JF, et al. Norfolk QOL-DN: validation of a patient reported outcome 
measure in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst 2014; 19: 104-114. 
Waits RP, Yamada T, Uemichi T, et al. Low plasma concentrations of retinol-binding protein in 
individuals with mutations affecting position 84 of the transthyretin molecule. Clin Chem 1995; 41: 1288-
1291. 
Wei S, Episkopou V, Piantedosi R, et al. Studies on the metabolism of retinol and retinol-binding protein 
in transthyretin-deficient mice produced by homologous recombination. J Biol Chem 1995; 270: 866-870. 
Westfall PH Young SS. Resampling-based Multiple Testing: Examples and Methods for p-Value 
Adjustment. In: Wiley Series in Probability and Statistics.  John Wiley & Sons Inc.  New York; 1993: 1-
360. 
Yazaki M, Mitsuhashi S, Tokuda T, et al. Progressive wild-type transthyretin deposition after liver 
transplantation preferentially occurs onto myocardium in FAP patients. Am J Transplant 2007; 7: 235-
242. 
Yazaki M, Tokuda T, Nakamura A, et al. Cardiac amyloid in patients with familial amyloid 
polyneuropathy consists of abundant wild-type transthyretin. Biochem Biophys Res Commun 2000; 274: 
702-706. 
Yu RZ, Graham MJ, Post N, et al. Disposition and Pharmacology of a GalNAc3-conjugated ASO 
Targeting Human Lipoprotein (a) in Mice. Mol Ther Nucleic Acids 2016a; 5: 1-10. 
Yu RZ, Gunawan R, Post N, et al. Disposition and Pharmacokinetics of a GalNAc3-Conjugated 
Antisense Oligonucleotide Targeting Human Lipoprotein (a) in Monkeys. Nucleic Acid Ther 2016; 26: 
372-380. 
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man of a 
second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug 
Metab Dispos 2007; 35: 460-468. 
 
 
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14. 
APPENDICES 
 
Appendix A Schedule of Procedures  
Appendix B List of Laboratory Analytes 
Appendix C PK Sampling Schedule  
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities  
 
 
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APPENDIX A. SCHEDULE OF PROCEDURES 
 
Treatment Period  
Post-Treatment Evaluation Period  
 
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Appendix A Schedule of Procedures Continued 
Legend Continued 
 
3 Full physical exam to be given at Screening and abbreviated physical exam to be given during Treatment and Post 
Treatment- Period as indicated to assess changes from Screening. 
4 The mNIS+7 assessment procedure includes:  NIS, QST, HRDB and pre-determined sensory and nerve conduction 
testing.  Additional clinical evaluations done during mNIS+7 assessment include:  Lower Limbs Function Test (LLF) 
and NSC.  Two (2) independent mNIS+7 assessments will be performed at selected visits on separate days.  Both 
Baseline mNIS+7 assessments should be performed within 21 days prior to the first dose of ION-682884 or inotersen 
(Day 1).  In addition, every effort should be made to conduct the 2 assessments < 7 days apart. 
 For an individual patient, every effort should be made to use the same mNIS+7 evaluator throughout the study and the 
evaluator must be insulated from the patient’s general study procedures and knowledge of the patient’s AEs.  Norfolk 
QOL-DN must be administered prior to any other study procedures.  At Baseline and Week 66, the Norfolk QOL-DN 
can be administered on the same day as the first mNIS+7 assessment.   
5 Transthoracic ECHO can be completed with ± 21-day window around Week 35, 66, 85 and 105 visits. 
6 For determination of patient eligibility only if appropriate documentation is not available.   
7 Screening Labs include FSH (for confirmation of menopause as per Inclusion Criteria 3 ii), HIV, HBV and HCV, 
SPEP and UPEP with immunofixation, serum free light chain ratio, and HbA1C per Appendix B. 
8 Conducted only in women who are of child-bearing potential per Inclusion Criterion 3 iv.  Pregnancy test should be 
conducted on serum or plasma samples at Screening and during in-clinic visits.  During visits at home, pregnancy test 
can be conducted on urine or serum/plasma.  However, on Day 1, pregnancy test should be conducted by urine as well 
as serum/plasma so that a negative urine test is available prior to dosing. 
9 If chemistry, hematology or urinalysis results are uninterpretable (e.g., due to clumping, hemolysis or quantity not 
sufficient) or missing, a repeat sample should be collected as soon as possible (ideally within 7 days).  The window for 
sample collections that occur outside clinic visits is ± 4 days.  See Section 8.5 for guidance on ION-682884 or 
inotersen dosing relative to chemistry, hematology or urinalysis monitoring. After the last dose (Week 81), monitoring 
should be performed every 4 weeks for 8 weeks (until Week 89, inclusive), either by Chemistry, Hematology or 
Urinalysis panel or by Abbreviated Monitoring panel. 
10  Collection of laboratory samples for vitamin A/Retinol testing should precede the ingestion of vitamin A supplement 
for that day. 
11  Stored at least at -70 °C for follow-up exploration of PD, laboratory findings (including disease biomarkers not 
specified in this protocol) and/or AEs (e.g., measurement of cytokine and/or chemokine levels, measurement of 
additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of 
ION-682884. 
12 The collection of the blood sample for potential follow up exploration of laboratory findings, AE, or disease 
progression in this or subsequent clinical studies of ION 682884 (not for genetic research) is expected for all patients, 
collection can only proceed if supported by local regulations and after patient consent 
13 The window of drug administration is ± 1 week for ION-682884, and ± 4 days for inotersen.  
14 On Weeks 5, 9, and 33, in-clinic visits are encouraged but not mandated.  If in-clinic visit is not done, Investigator 
must communicate with patients by phone or telemedicine tools where available to go over concomitant medications, 
AEs/SAEs and their general health.  Physical exam may be skipped per Investigator judgment.  A home health care 
provider can collect lab samples, VS, and ensure proper dosing of the Study Drug. If not in-clinic, PK and 
immunogenicity samples may be skipped.  If patient is part of PK subset, then Week 33 is mandatory to be in-clinic.  
15  ECG before first dose can be performed and assessed by Investigator anytime between Screening up to Day 1 visit as 
long as it is performed before the first dose. 
16 If results are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or missing, a repeat sample 
should be collected as soon as possible (ideally within 7 days).  The window for sample collections that occur outside 
clinic visits is ± 4 days.  See Section 8.5 for guidance on ION-682884 or inotersen dosing relative to platelet 
monitoring. After the last dose of inotersen (Week 34), monitoring should be performed every 2 weeks for 8 weeks 
(until Week 42, inclusive), either by Chemistry, Hematology or Urinalysis panel or by Abbreviated Monitoring panel. 
 
 
Time (time is in reference to ION‑682884 or inotersen administration) 
a  Pre-dose 
b 1, 2, 3, 4, 6 hours for PK subgroup only  
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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 ION‑682884 or other similar 
oligonucleotides. 
Chemistry Panel 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN 
Creatinine 
eGFR 
Cystatin C 
Uric Acid 
Total bilirubin 
Direct (conjugated) bilirubin 
Indirect (unconjugated) 
bilirubin 
ALT 
AST 
ALP 
Gama-Glutamyl Transferase  
Creatine kinase 
 
Immunoglobulins 
Total IgG 
Total IgM 
 
Screening Tests 
Hepatitis B surface antigen 
Hepatitis C antibody 
HIV antibody 
FSH (women only) 
HbA1c 
SPEP with immunofixation 
UPEP with immunofixation 
Serum free light chain ratio 
 
Pregnancy Test1  
Serum hCG or urine hCG 
 
Coagulation  
aPTT (sec) 
PT (sec) 
INR 
 
 
Other5 
Serum Tranthyretin 
Retinyl Palmitate (fasting) 
Serum Vitamin A   
Neurofilament Light Chain 
Neurofilament Heavy Chain  
 
Hematology 
Red blood cells 
Hemoglobin 
Hematocrit 
MCV, MCH, MCHC, RDW, MPV 
Platelets 
White blood cells 
WBC Differential (% and absolute) 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
 
Thyroid Panel 
TSH 
Free T4 (FT4)4 
Total T3 (TT4)4 
 
Pharmacokinetics2 
ION-682884 in plasma 
Inotersen in plasma 
 
Immunogenicity 
Anti-ION-682884 antibodies 
Anti-inotersen antibodies 
 
Cardiac Biomarkers  
NT-proBNP 
High-sensitivity Troponin T 
CK-MB 
Inflammatory5 
hs-CRP  
 
Urinalysis5 
Color 
Appearance 
Specific gravity 
pH 
UPCR and UACR 
Protein 
Blood 
Ketones 
Urobilinogen 
Glucose 
Bilirubin 
Leukocyte esterase 
Nitrate 
Microscopic examination3 
 
Abbreviated Monitoring 
Panel 
Total bilirubin, 
direct bilirubin, 
indirect bilirubin, 
ALT, AST, ALP, BUN, 
creatinine, eGFR, 
Cystatin C, UPCR, Platelets 
  
1 Conducted only in women who are of child-bearing potential per Inclusion Criterion 3 iv.  Pregnancy test should be 
conducted on serum or plasma samples at Screening and during in-clinic visits.  During visits at home, pregnancy test 
can be conducted on urine or Serum/plasma. 
2 Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation purposes, 
stability assessments, metabolite assessments, immunogenicity testing (or possibly for purposes of immunogenicity 
assay development and/or validation) or to assess other actions of ION-682884 with plasma constituents 
3 Will be performed on abnormal findings unless otherwise specified 
4 To be measured if TSH is outside of normal range 
5 Other biomarkers may be measured, as needed; at the discretion of the Sponsor.  Back-up samples will be collected and 
stored.  For transthyretin, back-up samples may be analyzed in more sensitive transthyretin assays at the discretion of 
the Sponsor.  Back-up urine samples may be analyzed for additional renal biomarkers 
 
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ION-682884-CS3 
CONFIDENTIAL 
Amendment 5
Protocol 
12 August 2021
 
100 
APPENDIX C. PK SAMPLING SCHEDULE 
 
 
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ION-682884-CS3 
CONFIDENTIAL 
Amendment 5
Protocol 
12 August 2021
 
101 
Appendix C PK Sampling Schedule  
All Patients except PK Subgroup Patients  
W1 
W5 
W13 
W25 
W33 
W35 
W49 
W57 
W65 
W66 
W73 
W81 
W85 
W93 
W105 
D1 
D29 
D85 
D169 
D225 
D239 
D337 
D393 
D449 
D456 
D505 
D561 
D589 
D645 
D729 
Pre-dose Pre-dose Pre-dose Pre-dose Pre-dose Anytime Pre-dose Pre-dose Pre-dose Anytime Pre-dose Pre-dose Anytime Anytime 
Anytime 
 
PK Subgroup Only 
W1 
W5 
W13 
W25 
W33 
W35 
W49 
W57 
W65 
W66 
W73 
W81 
W85 
W93 
W105 
D1 
D29 
D85 
D169 
D225 
D239 
D337 
D393 
D449 
D456 
D505 
D561 
D589 
D645 
D729 
Pre-dose, 1, 2, 
3, 4, and 
6 hours post-SC 
injection 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-dose, 1, 2, 3, 
4, and 6 hours 
post-SC injection 
Anytime Pre-
dose 
Pre-
dose 
Pre-dose, 1, 2, 
3, 4, and 
6 hours post-SC 
injection 
Anytime Pre-
dose 
Pre-
dose 
Anytime Anytime Anytime 
SC = subcutaneous 
D = Day  
W = Week 
 
682884-CS3 Protocol Amendment 5-12Aug2021-ROW | 1.0


ION-682884-CS3 
CONFIDENTIAL 
Amendment 5
Protocol 
12 August 2021
 
102 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES 
 
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ION-682884-CS3 
CONFIDENTIAL 
Amendment 5
Protocol 
12 August 2021
 
103 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities and 
adverse events at the injection site are based upon the CTCAE Version 5.0, November 2017 
 
 
 
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ION-682884-CS3 
CONFIDENTIAL 
Amendment 5
Protocol 
12 August 2021
 
104 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
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ION-682884-CS3 
CONFIDENTIAL 
Amendment 5
Protocol 
12 August 2021
 
105 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
682884-CS3 Protocol Amendment 5-12Aug2021-ROW | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
ION-682884-CS3 
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy 
and Safety of ION-682884 in Patients with Hereditary Transthyretin-
Mediated Amyloid Polyneuropathy 
Statistical Analysis Plan 
Final Version: 2.1 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 2 of 3 
SPONSOR SIGNATURE PAGE 
 
Approved by: 
 
 
 
 
 
 
 
 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0




PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 4 of 5 
TABLE OF CONTENTS 
1 
INTRODUCTION ..................................................................................................... 12 
2 
STUDY OBJECTIVES ............................................................................................. 12 
2.1 
Primary Objective ................................................................................................. 12 
2.2 
Secondary Objectives ............................................................................................ 13 
2.3 
Safety Objectives .................................................................................................. 13 
2.4 
Additional/Exploratory Objectives ....................................................................... 13 
2.4.1 
Efficacy Objectives ............................................................................................. 13 
2.5 
PK Objectives ....................................................................................................... 14 
3 
INVESTIGATIONAL PLAN ................................................................................... 14 
3.1 
Overall Study Design and Plan ............................................................................. 14 
3.2 
Study Endpoints .................................................................................................... 14 
3.2.1 
Interim Analysis Co-Primary Efficacy Endpoints at Week 35 ........................... 14 
3.2.2 
Interim Analysis Key Secondary Efficacy Endpoint at Week 35 ....................... 14 
3.2.3 
Final Analysis Co-Primary Efficacy Endpoints ................................................. 14 
3.2.4 
Final Analysis Secondary Endpoints .................................................................. 15 
3.2.5 
Safety Endpoints ................................................................................................. 15 
3.2.6 
Additional/Exploratory Endpoints ...................................................................... 15 
3.2.6.1 
Efficacy Endpoints ........................................................................................... 15 
3.2.6.2 
Pharmacokinetic Endpoints .............................................................................. 16 
3.3 
Trial Design Considerations .................................................................................. 16 
3.3.1 
Background ......................................................................................................... 16 
3.3.2 
Risks of bias and mitigation of bias .................................................................... 16 
4 
STATISTICAL METHODS ..................................................................................... 20 
4.1 
Data Management and Quality Assurance ............................................................ 20 
4.1.1 
Laboratory Data .................................................................................................. 21 
4.1.2 
Biomarker Data ................................................................................................... 21 
4.1.3 
PK Data ............................................................................................................... 21 
4.1.4 
Echocardiogram (ECHO) Data ........................................................................... 21 
4.1.5 
ECG Data ............................................................................................................ 22 
4.1.6 
mNIS+7,  NSC Score, and Norfolk  ................................................................... 22 
4.1.7 
SF-36 Data and Scoring ...................................................................................... 22 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 5 of 6 
4.1.8 
Medical Coding Data .......................................................................................... 22 
4.2 
General Presentation Considerations .................................................................... 23 
4.2.1 
Baseline ............................................................................................................... 24 
4.2.1.1 
Baseline for ION-682884 and inotersen ........................................................... 24 
4.2.1.2 
ION-682884 Baseline for patients received inotersen at the beginning of study 
and scheduled to switch to ION-682884 at Week 37 ....................................... 25 
4.2.2 
Definitions and Computational Formulas ........................................................... 25 
4.2.3 
Analysis Visit Windows ..................................................................................... 25 
4.3 
Software ................................................................................................................ 27 
4.4 
Study Subjects ....................................................................................................... 27 
4.4.1 
Disposition of Subjects ....................................................................................... 27 
4.4.2 
Protocol Deviations ............................................................................................ 27 
4.5 
Analysis Sets ......................................................................................................... 28 
4.5.1 
Screened Patients ................................................................................................ 28 
4.5.2 
Randomized Set .................................................................................................. 28 
4.5.3 
Full Analysis Set (FAS) ...................................................................................... 28 
4.5.4 
Per Protocol Set (PPS) ........................................................................................ 28 
4.5.5 
Safety Set ............................................................................................................ 28 
4.5.6 
PK Set ................................................................................................................. 29 
4.6 
Demographic and Other Baseline Characteristics ................................................ 29 
4.7 
Medical History ..................................................................................................... 30 
4.8 
Concomitant Medication ....................................................................................... 30 
4.9 
Treatment Exposure and Compliance ................................................................... 31 
4.10 
Efficacy Evaluation ............................................................................................... 32 
4.10.1 
Analysis and Data Conventions .......................................................................... 32 
4.10.1.1 Multi-center Study ............................................................................................ 38 
4.10.1.2 Adjustments for Covariates .............................................................................. 38 
4.10.1.3 Handling of Dropouts or Missing Data ............................................................ 38 
4.10.1.4 Data Summary Plan .......................................................................................... 42 
4.10.1.5 Interim Analysis and Multiplicity .................................................................... 44 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 6 of 7 
4.10.2 
Primary Efficacy Variable .................................................................................. 47 
4.10.2.1 Primary Endpoint Analysis at Interim Analysis ............................................... 47 
4.10.2.2 Secondary Endpoint Analysis at Interim Analysis ........................................... 49 
4.10.2.3 Primary Analysis at Week 66 Final Analysis ................................................... 49 
4.10.3 
Additional Analyses of Primary Endpoints ........................................................ 50 
4.10.3.1 Sensitivity Analyses ......................................................................................... 50 
4.10.3.2 Multiple Imputation Methodology ................................................................... 51 
4.10.4 
Subgroup Analyses of Primary Endpoints .......................................................... 53 
4.10.5 
Secondary Efficacy Variables for Week 66 Final Analysis ............................... 54 
4.10.6 
Pharmacodynamic Analysis ................................................................................ 54 
4.10.7 
Exploratory Analyses .......................................................................................... 55 
4.11 
PK and IM Analysis .............................................................................................. 56 
4.11.1 
PK Analysis ........................................................................................................ 56 
4.11.1.1 Plasma Concentration Data .............................................................................. 56 
4.11.2 
Plasma PK Parameters ........................................................................................ 56 
4.11.3 
IM Analysis ........................................................................................................ 57 
4.11.3.1 Sample Level ADA Data .................................................................................. 58 
4.11.3.2 Subject Level ADA Data .................................................................................. 58 
4.11.3.3 Evaluation of IM Impact on PK, PD, Efficacy and Safety ............................... 60 
4.12 
Safety Evaluation .................................................................................................. 60 
4.12.1 
Adverse Events ................................................................................................... 61 
4.12.1.1 Adverse Events of Special Interest (AESI) ...................................................... 63 
4.12.1.2 Other Adverse Events of Interest (OAEI) ........................................................ 64 
4.12.1.3 Injection Site Reaction (ISR) and Local Cutaneous Reactions at Injection Site 
(LCRIS) 
 ..................................................................................................... 66 
4.12.1.4 Flu-Like Reactions ........................................................................................... 66 
4.12.1.5 Renal Safety ..................................................................................................... 67 
4.12.2 
Clinical Laboratory Evaluation ........................................................................... 67 
4.12.2.1 Hepatobiliary Laboratory abnormalities .......................................................... 68 
4.12.2.2 Platelets 
 ..................................................................................................... 70 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 7 of 8 
4.12.2.3 Renal parameters .............................................................................................. 71 
4.12.3 
Vital Signs, Weight, and Physical Findings ....................................................... 72 
4.12.4 
12-Lead Electrocardiograms (12-Lead ECG) ..................................................... 73 
4.12.5 
Pregnancy ........................................................................................................... 74 
4.12.6 
Ocular Questionnaire .......................................................................................... 74 
4.12.7 
Safety Monitoring (Data and Safety Monitoring Board [DSMB]) ..................... 75 
4.13 
Determination of Sample Size .............................................................................. 75 
4.14 
Changes in the Conduct of the Study or Planned Analysis ................................... 75 
5 
REFERENCES .......................................................................................................... 76 
6 
Appendix ................................................................................................................... 77 
6.1 
Components and Subcomponents of the mNIS+7 ................................................ 77 
6.2 
Scoring of Assessment Instruments ...................................................................... 82 
6.3 
Composite Autonomic Symptom Score (COMPASS-31) .................................... 83 
6.4 
Sample Programming code for Final Alpha ......................................................... 86 
6.5 
Laboratory Parameters’ Classification by CTCAE v5.0 ....................................... 89 
6.6 
List of Changes in the Statistical Analysis Plan  .................................................. 93 
 
 
 
 
 
 
 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 10 of 11 
GLS 
Global longitudinal strain 
hATTR-PN 
Hereditary transthyretin-mediated amyloid polyneuropathy 
HLT 
Higher level term 
HP 
Heat pain 
HRDB 
Heart Rate to Deep Breathing 
IEC 
Independent ethics committee 
IM 
Immunogenicity 
INR 
International normalized ratio 
IRB 
Institutional review board 
IVS 
Intraventricular septum 
J2R 
Jump to reference 
LCRIS 
Local cutaneous reactions at injection site 
LLOQ 
Lower limit of quantification  
LV 
Left ventricular 
MAR 
Missing at Random 
MB 
Major bleeding 
mBMI 
Modified body mass index 
MC Core 
Mayo Clinic Polyneuropathy Quality Assurance Core Facility 
MCS 
Mental component summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mental Health 
MMRM  
Mixed effects model with repeated measures 
mNIS+7 
Modified neuropathy impairment Score +7. Standard NIS+7 but with 
modifications made to the +7 component 
Modified +7 
+7 test with modifications made to the sensory and nerve conduction 
testing 
NCT 
Nerve Conduction Test 
NEURO-TTR 
ISIS 420915-CS2 
NIS 
Neuropathy impairment score 
NIS-C 
Neuropathy impairment score – Cranial Nerves 
NIS-R 
Neuropathy impairment score – Reflexes 
NIS-S 
Neuropathy impairment score – Sensation 
NIS-W 
Neuropathy impairment score – Muscle Weakness 
Norfolk QOL-DN 
Norfolk quality of life questionnaire-diabetic neuropathy 
NSC 
Neuropathy symptoms and change 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
OLE 
Open-label extension 
P25 
25th percentile 
P75 
75th percentile 
PCS 
Physical component summary 
PD 
Pharmacodynamic 
PF 
Physical functioning 
PGIC 
Patient Global Impression of Change 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 11 of 12 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PMAK 
Fibular CMAP amplitude 
PMCVK 
Fibular nerve motor conduction velocity 
PMLA 
Fibular nerve distal latency 
PND 
Polyneuropathy disability 
PPS 
Per Protocol Set 
PT 
Preferred term 
QTc 
QT interval corrected for heart rate 
QTcB 
QTc interval calculated using Bazett's formula 
QTcF 
QTc interval calculated using Fridericia’s formula 
RE 
Role-Emotional 
R-ODS 
Rasch-built Overall Disability Score  
RP 
Role-Physical 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard error 
SF 
Social Functioning 
SF-36 
Short Form (36) Health Survey 
SMQ 
Standardized MedDRA query 
SOC 
System Organ Class 
SS 
Safety set 
SSAB 
Sural SNAP amplitude 
Study Day 1 
Defined as the first day Study Drug is administered to the patient 
Study Drug 
ION-682884 or inotersen 
TEAE 
Treatment emergent adverse event 
tmax 
Time to reach Cmax; obtained directly from the plasma concentration-
time profile 
TMLA 
Tibial nerve distal latency 
TP 
Touch pressure 
TTP 
Thrombotic thrombocytopic purpura 
TTR 
Transthyretin 
ULN 
Upper limit of normal  
UPCR 
Urine protein/creatinine ratio 
VAS 
Visual analog scale 
VT 
Vitality 
WHO-DD 
World Health Organization-Drug Dictionary 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
ION-682884-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
 Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019 
 Page 12 of 13 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications for the Tables, Listings and 
Figures. It describes the variables and populations, anticipated data transformations and 
manipulations and other details of the analyses not provided in the Clinical Study Protocol.  
The analyses described in this SAP are based upon the following study documents: 
•
Amendment 4 - Japan
20-Nov-20
•
Amendment 5 - Canada
19-Aug-21
•
Amendment 5 - Turkey
27-Aug-21
•
Amendment 5 – ROW
12-Aug-21
•
Amendment 6 - USA Only     18-Aug-21
•
Amendment 6 - Sweden
23-Aug-21
•
Amendment 6 - Germany 
28-Sep-21
•
Amendment 6 – Spain
26-Aug-21
•
Amendment 7 - France
18-Aug-21
•
Electronic Case Report Form (eCRF), Version 8.0 (December 22, 2021)
Section 2 indicates the study objectives. Section 3 provides overall study design and study 
endpoints. Section 4 presents statistical methods, including general guidelines to be followed for 
all analyses, the analysis population, handling of missing data, definition of Baseline and visit 
window, discussion for the primary/secondary efficacy and the sensitivity analyses, and details for 
pharmacodynamic (PD) endpoints and pharmacokinetic (PK) analyses.  
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of ION-682884 after administration 
for 65 weeks, as compared to the historical control of the placebo cohort in the ISIS 420915-CS2 
(NEURO-TTR) trial, based on the change from Baseline in serum transthyretin (TTR) 
concentration, modified Neuropathy Impairment Score +7 (mNIS+7), and in the Norfolk Quality 
of Life Questionnaire—Diabetic Neuropathy (Norfolk QOL-DN) in patients with hereditary 
transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN). 
An interim analysis will be conducted at Week 35. The interim analysis will be performed when 
all patients on ION-682884 complete Week 35 assessments, and will assess the efficacy (TTR, 
mNIS+7, Norfolk) compared to the placebo arm of the NEURO-TTR trial. 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 13 of 14 
2.2 
Secondary Objectives 
To evaluate the efficacy of ION-682884, as compared to the placebo cohort in the NEURO-TTR 
trial, based on the change from Baseline in the following measures: 
• Neuropathy Symptom and Change (NSC) score  
• Physical component summary (PCS) score of 36-Item Short Form Survey (SF-36) 
• Polyneuropathy disability (PND) score 
• Modified body mass index (mBMI) 
2.3 
Safety Objectives 
To evaluate safety and tolerability in hATTR-PN patients treated with ION-682884, including the 
change from Baseline in platelet count and renal function and the presence of adverse events (AEs). 
2.4 
Additional/Exploratory Objectives 
2.4.1 Efficacy Objectives 
To evaluate the efficacy of ION-682884 in mNIS+7 at Week 85, compared to Baseline. 
To evaluate the efficacy of ION-682884 in the change from Baseline in the Patient Global 
Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) at Weeks 37 and 
85. 
To evaluate the efficacy of ION-682884, as compared to the historical control of the 
placebo arm included in the ALN-TTR02-004 (APOLLO trial, ClinicalTrials.gov Identifier: 
NCT01960348), in the following measures: 
• Change from Baseline in Norfolk QOL-DN at Week 85 
• Change from Baseline in 10-Meter Walk Test (10MWT) at Weeks 37 and 81 
• Change from Baseline in Rasch-built Overall Disability Score (R-ODS) at Weeks 37 and 
81 
• Change from Baseline in Composite Autonomic Symptom Score-31 (COMPASS-31) at 
Weeks 37 and 81 
• Change from Baseline in 5-level EQ-5D version (EQ-5D-5L) at Weeks 37 and 81 
To evaluate the efficacy of ION-682884, as compared to the placebo cohort of the NEURO-TTR 
trial, in: 
• Change from Baseline in the SF-36 at Weeks 35 
• Frequency of all-cause hospitalizations (in all patients and in patients with cardiac 
involvement) by Week 66 
• Change from Baseline in transthoracic echocardiogram (ECHO) parameters, including left 
ventricular (LV) mass, LV wall thickness, intraventricular septum (IVS) thickness, and 
global longitudinal strain (GLS), in patients with cardiac involvement at Weeks 65. 
• Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) in patients 
with cardiac involvement at Weeks 65. 
• Change from Baseline in PGIS and PGIC at Week 37 and 85 
 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0




PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 15 of 16 
• Change from Baseline in mNIS+7 at Week 66  
• Change from Baseline in Norfolk QOL-DN at Week 66  
In the Week 66 Final Analysis, for those statistically significant endpoints at the Week 35 
interim analysis, their corresponding tests at the Week 66 final analysis will not be 
conducted (See Section 4.10.2.3).   
3.2.4 Final Analysis Secondary Endpoints 
• Change from Baseline in NSC at Weeks 66 
• Change from Baseline in NSC at Weeks 35 
• Change from Baseline in the PCS score of SF-36 at Week 65 
• Change from Baseline in PND score at Week 65 
• Change from Baseline in mBMI at Week 65 
3.2.5 Safety Endpoints 
• Change from Baseline in platelet count during the Treatment Period 
• Change from Baseline in renal function during the Treatment Period 
• Adverse events 
• Vital signs and weight 
• Physical examination 
• Clinical laboratory tests 
• Electrocardiogram (ECG) 
• Use of concomitant medication 
• Ophthalmology examination 
• Thyroid panel 
• Inflammatory panel 
• Coagulation 
• Immunogenicity 
3.2.6 Additional/Exploratory Endpoints 
3.2.6.1 Efficacy Endpoints 
• Change from Baseline in mNIS+7 at Week 85 
• Change from Baseline in Norfolk QOL-DN at Week 85 
• Change from Baseline in 10MWT at Weeks 37 and 81 
• Change from Baseline in R-ODS at Weeks 37 and 81 
• Change from Baseline in COMPASS-31 at Weeks 37 and 81 
• Change from Baseline in EQ-5D-5L at Weeks 37 and 81 
• Change from Baseline in the SF-36 components at Weeks 35 
• Frequency of all cause hospitalizations in all patients and in patients with cardiac 
involvement by Week 66 
• Change from Baseline in transthoracic ECHO parameters, including LV mass, LV wall 
thickness, IVS thickness, and GLS, in patients with cardiac involvement at Week 65 
• Change from Baseline in NT-proBNP in patients with cardiac involvement at Week 65 
• Change from Baseline in PGIS at Week 37 and 85 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 16 of 17 
• Change from Baseline in PGIC at Week 37 and 85 
 
3.2.6.2 Pharmacokinetic Endpoints 
Plasma trough and post-treatment concentrations of ION-682884 or inotersen in all patients; area 
under the curve (AUC), maximum observed plasma concentration (Cmax), and time to reach Cmax 
(tmax) obtained directly from the plasma concentration-time profile in a subset of patients (PK 
subgroup); and t½λz for patients who do not roll over to the OLE study. 
 
3.3 
 Trial Design Considerations 
3.3.1 Background  
ION-682884 is a ligand-conjugated antisense oligonucleotide (LICA), specifically a second-
generation 2′-MOE of twenty (20) nucleotides (i.e., a 20-mer) that are connected sequentially by 
phosphorothioate and phosphate diester internucleotide linkages and conjugated at the 5′ end to a 
triantennary N-acetyl galactosamine (GalNAc) moiety. GalNAc conjugation enhances the uptake 
of ASOs to hepatocytes, and thereby increases the potency of ASOs in humans up to approximately 
30-fold. The strategy for treatment of transthyretin-mediated amyloidosis (ATTR) with 
systemically delivered ION-682884 is to reduce levels of mutated and wild-type TTR protein 
secreted by the liver. This strategy has been validated by the successful Phase 2/3 NEURO-TTR 
study of Tegsedi (inotersen), an unconjugated 2′-MOE PS ASO which shares ION-682884’s 
nucleotide sequence, which demonstrated improvement in the course of neurologic disease and 
quality of life in patients with stage 1 and stage 2 hereditary ATTR with polyneuropathy (hATTR-
PN). 
Currently, two products are approved globally for the treatment of hATTR-PN: Tegsedi 
(inotersen), and Onpattro (patisiran), an RNAi product which also reduces levels of TTR protein, 
and which is administered intravenously. A third product, Vyndaqel (tafamidis), a tetrameric TTR 
stabilizer, is approved in some countries for treatment of symptomatic stage 1 hATTR-PN patients. 
Treatment with inotersen is associated with risks of severe thrombocytopenia and 
glomerulonephritis. 
In light of hATTR’s status as a rare disease, as well as the current highly competitive environment 
for recruitment of hATTR patients, the sponsor’s objective is to conduct a pivotal registration study 
which represents a scientifically valid assessment of ION-682884’s clinical efficacy in treatment 
of hATTR-PN, while also being sufficiently appealing to patients to both accrue the study within 
a reasonable time frame and retain all subjects throughout the treatment period. The concurrent 
reference cohort of patients receiving open-label inotersen in ION-682884-CS3 will be 
descriptively compared to the historical inotersen cohort of NEURO-TTR to validate efficacy 
comparisons between the two studies. 
3.3.2 Risks of bias and mitigation of bias 
Externally controlled studies face important risks of bias.  The design of the present study aims to 
mitigate these risks as follows, considering the framework provided by Pocock 1976 and E10 
guidance: 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 17 of 18 
This trial is a randomized open-label study that compares the active ION-682884 arm to historical 
control data from another trial. This design has several limitations compared to a double-blind, 
randomized, placebo-controlled trial. An open-label trial is subject to more bias when compared to 
a blinded trial, and data from two trials performed at different times leads to questions of the 
validity of such a comparison. The sponsor acknowledges these limitations, but believes this is a 
unique situation in which comparison to historical control is justified.  
Firstly, the historical control data were collected in a randomized, double-blinded, placebo-
controlled trial (NEURO-TTR) in the same disease population within the last 8 years by the same 
sponsor. The trial was accepted by multiple regulatory agencies and supported the approval of the 
drug inotersen. Secondly, as the study is being supported by many of the same sites and original 
study team members, similar mitigations and trial conduct will be employed in the current study. 
Finally, several measures have been instituted in the current trial to ensure the integrity of the trial 
conduct and validity of data comparison. They are listed below: 
Patient population:  
• 
Eligibility criteria are designed to mirror those in NEURO-TTR in defining hATTR-PN 
disease stage, age range, gender, exclusions of certain comorbidities, restriction of 
concomitant medications for hATTR and functional status. 
Sites and regions:  
• 
Sites that participated in NEURO-TTR are also participating in the current trial.  Additional 
sites and regions have been added to enhance enrollment; however, all of the selected sites 
have experience with hATTR disease management. Since this is a rare disease, participating 
clinicians are generally active in international congresses in which practice guidance and 
experiences are exchanged and aligned.   
• 
Oversight of sites by the study team, especially the new sites not involved in NEURO-TTR, 
will ensure that the trial conduct is as similar as possible to NEURO-TTR.  
 
Primary endpoint evaluation comparison.  
The primary endpoint evaluation is consistent between the NEURO-TTR and ION-682884-CS3 
studies. Measures have been taken to maximize the validity of the comparison. The primary 
endpoints of mNIS+7 and Norfolk QOL-DN will be masked to the sponsor team responsible for 
oversight of the study. Any team members that become unblinded at the time of interim analysis 
will be replaced with blinded team members.  Further details are described in the Unblinding and 
Data Access Plan.  Similarly to NEURO-TTR, the mNIS+7 central reader at PNRL, Mayo Clinic, 
will be blinded to treatment assignment. All mNIS+7 assessors will be blinded to the rest of trial 
conduct. For mNIS+7 evaluation, the conduct of the primary endpoint assessment is similar to 
NEURO-TTR, i.e., mNIS+7 assessors will be trained and certified by Dr. Peter Dyck, a neurologist 
at PNRL, Mayo Clinic, who created the composite score. Dr. Dyck’s team will be the central reader 
to review and normalize the results.  Pharmacodynamic markers will be blinded to sites and 
patients. 
 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 18 of 19 
Open-label bias for endpoints.  Patient- or clinician-reported outcomes may incur response bias 
in open-label designs.  To assess this risk for key outcome measures, we visually inspected the 
effect of inotersen on changes in mNIS+7 and Norfolk QoL during the double-blind period in 
NEURO-TTR, and crossover from placebo to open-label inotersen in the NEURO-TTR OLE study 
(see figures below).  Open-label bias was not visually evident based on the fact that the slope of 
disease progression is similar before and after the change to open label. Furthermore, although 
participants are not blinded to treatment assignment, the primary outcome assessments of serum 
TTR reduction and mNIS+7 scores are largely objective, and no formal statistical comparison will 
be made between the reference inotersen arm and the ION-682884-treated arm. 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 20 of 21 
reactions will be analyzed by definitions that are designed to identify clinically relevant cases and 
are defined identically between NEURO-TTR and ION-682884-CS3. The Adverse Events of 
Special Interest (AESI) and Other Adverse Events of Interest (OAEI) are the same between 
NEURO-TTR and ION-682884-CS3, with the exception that a renal impairment AESI has been 
moved to OAEI and replaced with glomerulonephritis AESI, a cardiac OAEI has been added.  
The complement activation was removed because using the hypersensitivity SMQ was not very 
specific to compliment activation and in NEURO-TTR did not show any differences from 
placebo. The Cardiac OAEI uses standard MedDRA terms so can be applied to both the ION-
682844 and comparator arms consistently 
Baseline factor adjustment.   The following baseline factors will be used in the propensity score 
for baseline factor adjustment based on the NEURO-TTR analysis: disease stage, previous 
treatment, and V30M mutation. In addition to the three factors used in the primary analyses, some 
sensitivity analyses may include the following factors in the logistic model for the propensity score.    
• 
Gender (Male, Female) 
• 
Modified BMI baseline (continuous value) 
• 
Region (Europe, North America, South America/Australasia/Asia) 
For the MMRM and ANCOVA analyses, baseline result of the endpoint will be used as the 
covariate, if applicable. 
 
4 
STATISTICAL METHODS 
4.1 
Data Management and Quality Assurance 
ICON plc (nee PRA) has been contracted to provide Data Management services for this study. As 
part of the contract, ICON (nee PRA) is responsible for creating the Medidata RAVE Electronic 
Data Capture (EDC) data entry screens, database and edit checks using definitions developed 
together with Ionis Pharmaceuticals, Inc. In addition to database development, ICON (nee PRA) 
is also responsible for the clinical database maintenance throughout the course of the study (i.e., 
amendments), as well as for the review, data management querying, and locking of the database. 
Data are single-entered into the EDC system by the investigator site staff. Programmed edit checks 
(computer logic that checks the validity of the data entered and also prompts for missing data that 
are expected to be entered) are run at the time of data entry within EDC, and automatic queries are 
generated. ICON (nee PRA) reviews all data for accuracy and validity and generates additional 
manual queries in the EDC system when necessary. The data are corrected, or an explanation 
concerning the query is provided in the EDC system and saved in the audit trail. 
Exceptions for data entry are protocol deviations entered by the ICON (nee PRA) monitors, and 
mNIS+7 data, which are entered into the EDC by an independent contract research group, the Mayo 
Clinic Polyneuropathy Quality Assurance Core Facility (MC Core), which is under the direction 
of Dr. Peter Dyck. These mNIS+7 eCRFs are restricted from review by both ICON (nee PRA) and 
Ionis Pharmaceuticals, Inc. (Note that the CNA Booklet data at the Screening Visit is available for 
review by both ICON (nee PRA) and Ionis Pharmaceuticals, Inc.).  
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 21 of 22 
For the purpose of data cleaning, a firewalled data manager at the CRO contracted to perform data 
management (TRENNIC Data Services) will have access to the post-baseline mNIS+7, NSC, 
Norfolk-QOL-DN. This data manager will not communicate or discuss the firewalled data with the 
rest of Ionis team.  
After all data are entered, reviewed, and queried, the database is closed and sent to the statistics 
group for review and for identification of significant protocol deviations. After any further queries 
that arose from this review are resolved, the database is locked. Database interim locks will be 
done at Week 35, Week 66,  and after all patients have completed the EOT assessments. The final 
data base lock will be performed after all subjects complete the study, and is referred to as the end 
of study (EOS) final lock. Further details can be found in the Data Management Plan. 
 
4.1.1 Laboratory Data 
Ionis Pharmaceuticals, Inc. and ICON (nee PRA) are responsible for the format of the laboratory 
electronic data transfers and the transfer schedule.  Central laboratory, MedPace, data results are 
not stored in the EDC system. ICON (nee PRA) and Ionis Pharmaceuticals, Inc. 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).  Local laboratory results, if any, will be entered directly in EDC by site staff; 
monitors will review against laboratory reports and local laboratory normal reference ranges 
document, and ICON (nee PRA) data management team will perform standard data review of local 
laboratory results as well. 
4.1.2 Biomarker Data 
Immunologix Laboratories is contracted and responsible for analyzing Transthyretin (TTR), 
Neurofilament Light Chain (NfL) and Neurofilament Heavy Chain (NfH). Ionis Pharmaceuticals, 
Inc. is responsible for the format of the electronic data transfers and the transfer schedule. Ionis 
Pharmaceuticals, Inc. and ICON (nee PRA) are responsible for the data reconciliation of the results 
data. This process involves reviewing the patient and visit identifiers in the lab results data against 
the lab data collected in the EDC system.    
4.1.3 PK Data 
Ionis Pharmaceuticals, Inc. 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.   
4.1.4 Echocardiogram (ECHO) Data 
The Echocardiogram (ECHO) data will be collected, analyzed, and stored in a secure database by 
an independent Contract research organization (CRO) (Cardiac Imaging Core Laboratory and 
Clinical Trials Endpoints Center at the Brigham and Women’s Hospital [CICL]).  The sites will 
upload the echocardiogram (ECHO) data on a secure web-portal for analysis by CICL.  CICL will 
only inform the site whether the echo images are of acceptable quality or not. CICL will not provide 
a formal report, read, or clinical data to the sites. Echocardiogram (ECHO) results data are not 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 22 of 23 
stored in the EDC system.  Ionis Pharmaceuticals, Inc. and ICON (nee PRA) are responsible for 
the format of the echocardiographic electronic data transfers and the transfer schedule. Ionis 
Pharmaceuticals, Inc., and ICON (nee PRA) are responsible for the data reconciliation of the 
echocardiogram (ECHO) results data. This process involves reviewing the patient and visit 
identifiers in the echocardiogram (ECHO) results data against the echocardiogram (ECHO) data 
collected in the EDC system.    
4.1.5 ECG Data 
All ECG data (machine read after review by PI) are entered into the Medidata Rave EDC by the 
sites. The Rave EDC data will be used for ECG summary and analysis. 
4.1.6 mNIS+7, NSC Score, and Norfolk  
The primary efficacy assessment, mNIS+7 scores, will be collected and stored by an independent 
contract research group, Mayo Clinic Polyneuropathy Quality Assurance Core Facility (MC Core), 
which is under the direction of Dr. Peter Dyck.  The NSC score is obtained during the NIS 
assessment procedure and is also collected and stored by MC Core. The mNIS+7 results from each 
site will be transmitted via EDC to MC Core for processing and quality assurance. The mNIS+7 
data are retained and stored in EDC. All of the mNIS+7 data are entered by the MC Core into a 
restricted portion of the study EDC system. Only MC Core and the pre-identified Ionis data 
manager have unrestricted access to this portion of the EDC system.  The Sponsor and clinical sites 
do not have access to the MC Core portion of the EDC. The mNIS+7 summated score will not be 
shared with the sites until after the study is completed. Up until Week 35 interim analysis, the 
Sponsor will only have access to patient screening Total NIS Score and baseline visit data.    
The primary endpoints of mNIS+7 and Norfolk QOL-DN will be masked to the sponsor team 
responsible for oversight of the study and any team members that become unblinded at the time of 
interim analysis will be replaced with blinded team members.  
 
4.1.7 SF-36 Data and Scoring 
The 36-Item Short Form Survey (SF-36) will be entered in EDC by site staff, and monitored and 
data reviewed by ICON (nee PRA). Ionis Pharmaceuticals, Inc. data management is responsible 
for scoring the raw data entered in EDC using the Quality Metric PRO CoRE Smart Measurement 
System, PRO CoRE Version 2.1 software, and providing SF-36v2® Health Survey scored dataset 
to the statistics group for analysis. 
4.1.8 Medical Coding Data 
ICON (nee PRA) is responsible for coding Medical History entries, Adverse Events, as well as 
Concomitant Medications entered in EDC by site staff, using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary Version 25.0 or later version and WHODRUG Global 
B3 Mar2022 or later version, respectively. Data management will provide coded datasets to the 
statistics group for analysis. 
 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 23 of 24 
4.2 
General Presentation Considerations 
All tables will present the population frequencies in each treatment group and/or subgroup (where 
appropriate) and will indicate the number of subjects with non-missing data and the denominators 
for percentages.    
Continuous data will be summarized in terms of the mean, standard deviation (SD), standard error 
(SE), median, interquartile range (25th percentile [P25], 75th percentile [P75]), range (minimum, 
maximum) and number of observations, unless otherwise stated. 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, upper quartile, least squares means and difference in least squares 
means will be reported to one more decimal place than the raw data recorded in the database. The 
SD and SE 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. All raw values presented in listings will be displayed to the measured precision.   
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages.  Any planned collapsing of categories 
will be detailed in the text and the data displays.   
Age will be presented in years. Weight will be presented in kg. Height will be presented in cm. 
Temperature will be presented in °C. Laboratory values will be summarized using standard units. 
Percentages will be presented to one decimal place and 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. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-
values less than 0.001 will be presented as “<0.001”. All statistical tests will be conducted using 
2-sided tests with 5% Type I error rates, unless otherwise stated. 
Confidence intervals will be presented to one more decimal place than the raw data. 
Summaries of plasma drug concentrations and pharmacokinetic parameters will include typical 
descriptive statistics, such as n, mean, SD, SE, percent Coefficient of Variation (%CV), geometric 
mean, geometric %CV, median, minimum, and maximum.   
All eCRF data, lab data transfers, mNIS+7 score data, as well as any outcomes derived from the 
data, will be provided in the patient data listings. Patient data listings will be presented for all 
patients enrolled into the study. 
All primary, secondary and PD endpoints will be assessed on the Full Analysis Set (FAS) and Per-
Protocol Set (PPS), with the former being the basis for the primary efficacy analysis. All safety 
assessments will be performed on the Safety Set (SS). PK endpoints will be assessed in the PK Set 
as applicable. 
The reference arm (inotersen) will be summarized descriptively with the NEURO-TTR inotersen 
arm.  No formal statistical comparison will be made between the reference arm and the ION-
682884-treated arm. 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 24 of 25 
Efficacy results will be summarized under the treatment to which patients were 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 and PD 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 procedures. 
All the missing visit or missing data related to COVID-19 will be listed.  Additional listings will 
be provided for the patients’ assessments with COVID-19 impact.  Additional summary will be 
provided if deemed necessary.   
 
4.2.1 Baseline 
4.2.1.1 Baseline for ION-682884 and inotersen 
The same Baseline definitions as in the NEURO-TTR trial will be applied in this study. The 
Baseline for efficacy, PD, and safety assessments will be defined as follows: 
• Baseline mNIS+7 and its individual components will be defined as the average of 2 
assessments taken within 60 days prior to the first dose of ION-682884 or inotersen. If only 
one assessment has been done, the single assessment will be used in place of the average. 
Rarely, for patient convenience, the Baseline mNIS+7 assessment(s) (or a subset of this 
assessment) will have been completed early in the Treatment Period rather than pre-
treatment. These will be considered protocol deviations. These assessments will be 
included in the analysis as valid Baseline assessments, provided they are taken within 1 
week after the first dose. The rationale for this is that the pharmacology of the drug indicates 
that the drug will have no effect on mNIS+7 this early in treatment, and including these 
values as the Baseline assessments will allow these patient’s data to be included in the 
primary analysis. 
• Baseline NSC and individual components will be defined as the average of 2 assessments 
taken within 60 days prior to the first dose of ION-682884 or inotersen. If only 1 assessment 
has been done, the single assessment will be used in place of the average. Because NSC 
score is collected during the NIS assessment procedure, it is possible it could be completed 
early in the Treatment Period rather than pre-treatment. These will be considered protocol 
deviations. These assessments will be included in the analysis as valid Baseline assessments 
provided they are taken within 1 week after the first dose. 
• Baseline ECG will be defined as the value taken on Day 1 pre-dose. If the triplicates are 
taken, the average of the triplicates will be used.  If only 1 or 2 assessments are available, 
the single assessment or average of the 2 assessments will be used. If the case that Day 1 
pre-dose ECG is missing, screening visit results will be used as Baseline. 
• Baseline for numerical laboratory assessment including PD will be defined as the average 
of all non-missing pre-dose assessments.  
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 25 of 26 
Baseline for all other assessments will be defined as the last non-missing value prior to the first 
dose of study drug (ION-682884 or inotersen). 
Of note, for re-consented and re-screened patients, only records after re-screening will be used 
for Baseline. 
 
4.2.1.2 ION-682884 Baseline for patients received inotersen at the beginning of study and 
scheduled to switch to ION-682884 at Week 37 
ION-682884 baseline will be defined as the last non-missing assessment prior to the first dose of 
ION-682884.  
 
4.2.2 Definitions and Computational Formulas 
The same on-treatment period definitions as in the NEURO-TTR trial for efficacy and PD data will 
be applied in this study.  
• Day 1 will refer to the day of the first dose of study drug.  
• For efficacy endpoints except for BMI and mBMI: 
o The efficacy on-treatment period spans the time during which the study treatment is 
administered until 52 days after the last dose of medication.   
o The efficacy post-treatment period starts on the day after the efficacy on-treatment period 
and ends on the day of the patient’s last contact date within the study. 
• For BMI, mBMI, and PD endpoints: 
o The on-treatment period spans the time during which the study treatment is administered 
until 28 days after the last dose of medication.  
o The post-treatment period starts on the day after the on-treatment period and ends on the 
day of the patient’s last contact date within the study. 
• For safety endpoints, the safety period spans the time drug is first administered until the day of 
the patient’s last contact date within the study. 
• The PK and Immunogenicity (IM) on-study period spans the time drug is administered until 
the day of the patient’s last contact date within the study.  
• Note: Assessments for mNIS+7, and NSC done early in the treatment period that are used for 
baseline cannot also be used as an on-treatment assessment.  
• Body mass index (BMI) will be computed using the formula: 
      BMI = (weight in kilograms) / [height in cm / 100]2 
• mBMI will be computed from BMI and serum albumin levels by: 
                      mBMI = BMI * serum albumin (g/L). 
 
4.2.3 Analysis Visit Windows 
For 682884-CS3 study, the efficacy and PD data will be assigned to a visit according to the visit 
windows in the table below. Efficacy assessments that occurred more than 52 days after the last 
dose of study drug will not be included in the efficacy analyses/summaries during the efficacy on-
treatment period, even if they occur within one of the visit windows. PD assessments, as well as 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 28 of 29 
Major protocol deviations will be summarized by deviation category. Additionally, protocol 
deviations related to COVID-19 will also be summarized by deviation category. 
 
4.5 
Analysis Sets 
The population definitions that will be used in this study are provided below and are very similar 
to those employed in the NEURO-TTR trial. The number of patients in each analysis population 
will be summarized by treatment group and overall for all randomized patients.   
4.5.1 Screened Patients 
Screened patients will be defined as those patients who signed an informed consent form. Screen 
failures and reason for failure will be summarized. 
4.5.2 Randomized Set 
The Randomized Set will be defined as those screened patients who received a randomization 
assignment. Results will be summarized under the treatment to which patients were randomized. 
4.5.3 Full Analysis Set (FAS) 
The Full Analysis Set will be defined as all randomized patients who received at least 1 injection 
of ION-682884 or inotersen and who have a Baseline and at least 1 post-Baseline efficacy 
assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For the NEURO-
TTR trial, the FAS included all randomized patients who received at least 1 injection of study drug 
and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or 
Norfolk QOL-DN questionnaire total score.  The FAS will be the primary population for analysis 
of efficacy and PD outcomes. Results will be summarized under the treatment to which patients 
were randomized. 
It is possible that the Week 66 final analysis FAS might be slightly different from the Week 35 
interim analysis FAS.  
4.5.4 Per Protocol Set (PPS) 
The Per Protocol Set is defined as those patients from the FAS who received at least 80% of 
prescribed injections of ION‑682884 or inotersen and who have no significant protocol deviations 
that would be expected to affect efficacy assessments. The PPS will be defined separately for Week 
35 interim analysis and Week 66 final analysis. The Week 35 interim analysis PPS will use only 
data up to week 35 while the Week 66 final analysis PPS will use all data up to Week 66.  
Summary of reasons for patients excluded from PPS will be provided.  Results will be summarized 
under the treatment to which the patients were randomized. 
4.5.5 Safety Set  
The Safety Set (SS) will be defined as all patients who are randomized and receive at least 1 dose 
of ION-682884 or inotersen. For the NEURO-TTR trial, the SS included all randomized patients 
who received at least 1 injection of study drug.  Results will be summarized under the treatment 
which the patients received. 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 29 of 30 
4.5.6 PK Set 
The PK Set will be defined as all patients who are randomized and receive at least 1 dose of ION-
682884 or inotersen and have at least 1 evaluable PK sample.  Results will be summarized under 
the treatment which the patients received. 
PK Subgroup: patients who will have additional PK samples collected on Days 1, 225 (Week 33) 
and 449 (Week 65).  Results will be summarized under the treatment which the patients received. 
 
4.6 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be descriptively summarized by treatment 
group for the Randomized Set, FAS, PPS, SS, and PK. Patient’s allocation by investigative site 
will be tabulated by treatment group and overall for the all enrolled patients. 
The following summary and listing will be provided: 
Patient demographic characteristics and Baseline severity of illness will be summarized by 
treatment group and overall for the Randomized Set, SS, FAS, PPS, and PK Set. Patient 
demographic characteristics, including age, age group (<65 years, 65-74 years, >=75 years), sex, 
race, ethnicity, country of site, TTR genotype category, duration of disease from hATTR-PN 
diagnosis (months), and duration from onset of hATTR-PN symptoms (months), criteria used to 
document the diagnosis of TTR cardiomyopathy (FAC), duration of disease from FAC diagnosis 
(months), and duration from onset of FAC symptoms (months), previous treatment and disease 
stage will be summarized by treatment group and overall for the SS, FAS, PPS, and PK subgroup. 
Baseline severity of illness, including the NIS score, mNIS+7, PND score, serum TTR, high-
sensitivity Troponin T, mBMI, BMI, weight, height, NYHA, and NT-proBNP, will be summarized 
by treatment group and overall for the SS, FAS, PPS and PK subgroup. Measures of quality of life 
and level of functioning, including the baseline Norfolk QOL-DN total score and SF-36, will also 
be included. 
The TTR genotype category will be summarized by V30M vs. Non-V30M.  The V30M genotype 
category includes V30M Mutation (‘Yes’) and VAL50MET, V50M MUTATION, V50M and 
P.VAL50MET listed under the “Other” category in CRF.   
The hATTR-PN/FAC diagnosis and onset date of hATTR-PN/FAC symptoms only collected year 
and month information in CRF. To facilitate the calculation of duration, the following imputation 
rules will be applied: 
• If year is missing, no imputation will be performed.   
• Day will be imputed as 01. 
• 
If month is missing and the recorded year is before the year in informed consent date, the 
missing month will be imputed to be December; otherwise, it will be imputed as the month 
from the informed consent date. 
A by-patient listing of demographics will be presented based on the SS. This will include the year 
of birth, age (in years), sex, race, ethnicity, height (in cm), weight (in kg) and BMI. The body 
weight will be the measurement obtained at Screening. 
 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 30 of 31 
4.7 
Medical History 
Medical history will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary Version 25.0 or later version and will be summarized by system organ class (SOC) and 
preferred term (PT), by treatment group and overall for the SS. Medical history will also be 
provided in the data listings.  
In addition, the CRF has a page for medical history of interest prompt. All medical history of 
interest collected in this CRF will be listed. 
 
4.8 
Concomitant Medication 
Medications will be coded using Anatomical Therapeutic Chemical (ATC) Classification codes by 
WHODRUG Global B3 Mar2022 or later. 
Prior and concomitant medications will be defined using the start and stop dates, and ongoing fields 
recorded in the Case report form (CRF) relative to the first and last dose dates of randomized study 
drug. A prior medication is defined as any medication taken up to, but not including the start date 
of study drug. A concomitant medication is defined as any medication taken whilst study drug is 
being taken.  
Note that if either of the start dates or stop dates of prior/concomitant medication are missing, the 
worst, i.e. most conservative, case will be considered when slotting medications (i.e., the 
medications should slot into all possible phases).  If a medication is administered pre-treatment or 
after first dose of study drug and no stop date/time is recorded, then usage will be assumed to be 
ongoing for the remainder of the data collection periods. If a medication is stopped on treatment 
or after first dose and no start date/time is recorded, it will be assumed that the medication was 
ongoing from prior to the start of study drug.  If a medication has no start or stop date, it will be 
assumed that the medication was ongoing from prior to the start of study drug. If a partial date is 
recorded in the case report form, the following convention will be used to assign the medication: 
• if the partial date is a start date, a '01' will be used for the day and 'Jan' will be used for the 
month 
• if the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent on the 
month and year) and 'Dec' will be used for the month. 
The recorded partial date will be displayed in listings.  
The definitions for prior, concomitant medication defined relative to use of study drug are shown 
schematically in the diagram below.  
Scenario 
First dose date 
Prior 
Medication 
Concomitant  
1 
x----------x 
 
Y 
N 
2 
      x------------------------x/* 
Y 
Y 
3 
 
x-------x/* 
N 
Y 
4 
?----------x 
 
Y 
N 
5 
      ?-------------------------x/* 
Y 
Y 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 32 of 33 
• Overall treatment compliance by groups (%): 
[Actual total dose infused (mg) in each treatment group /Expected total dose (mg) to be 
administered in each treatment group] *100. For patients who discontinued treatment, 
denominator should be (number of doses expected until discontinuation). 
This compliance will be analyzed by following treatment groups: 
- 
ION-682884 
- 
inotersen prior to Week 35 
- 
inotersen switch to ION-682884  
- 
NEURO-TTR Inotersen 
The overall actual total volume: sum of actual total volume of treatment by subject.  
The overall expected total volume: sum of expected total volume of treatment by subject.   
• Treatment compliance by categories (<80%, 80%-100%, 100%-120%, >120%) 
 
Duration of drug exposure (month) and total amount of ION-682884 administered (mg) will be 
summarized by baseline platelet count categories < 125 × 109/L, ≥ 125 to < 150 × 109/L, ≥ 150 to 
< 175 × 109/L, ≥ 175 to < 200 × 109/L, and ≥ 200 × 109/L. 
 
4.10 Efficacy Evaluation 
4.10.1 Analysis and Data Conventions 
TTR 
As part of the primary analysis, TTR levels at both baseline and postdosing will be compared to 
the levels in the placebo arm of the NEURO-TTR trial. During the NEURO-TTR trial, TTR levels 
in human serum were measured using a validated commercial pre-albumin assay from Roche, using 
an immunoturbidometric method. In the ION-682884-CS3 trial, a novel electrochemiluminescence 
(ECL) assay has been developed and validated to measure TTR levels in human serum. In order to 
enable valid cross-assay comparison of TTR levels from the two assays, a formula was created as 
part of cross-validation of the two methods, y=0.0057x^2 + 0.5843x - 0.3819 (data and derivation 
of the formula are provided in the method validation report TTR-BRV02). Accordingly, the 
immunoturbidometric serum TTR level data from the placebo arm in the NEURO-TTR trial will 
be converted using the formula y=0.0057x^2 + 0.5843x - 0.3819 to allow comparison to data 
generated by the current ECL assay. The converted value of the placebo arm data will then be used 
in the primary analysis.   
mNIS+7 
The mNIS+7 consists of two composite scores: the NIS composite score (maximum of 244 points) 
and the modified +7 composite score (maximum of 102.32 points).   
NIS 
The NIS composite score consists of 4 components: 
• Cranial Nerves (NIS-C), maximum 40 points 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 36 of 37 
standardized using a linear T-transformation to have a mean of 50 and a standard deviation of 10 
All norms and scoring algorithms used will be based on the US population norms. 
PCS and MCS will be set to missing if the patient is missing  any  of the eight SF-36 scales. 
The scoring of the SF-36 will be conducted using the Quality Metric PRO CoRE Smart 
Measurement System, PRO CoRE Version 2.1. 
NSC 
The NSC (version: 04Jan2009) questionnaire consists of one total score and five domains (muscle 
weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic 
(gastrointestinal and urinary incontinence), and autonomic (non-GI/non-urinary incontinence)). 
The muscle weakness domain is divided into four sub-domains (head and neck, chest, upper limbs, 
and lower limbs). The scoring of the NSC questionnaire is described in  Appendix 6.2. 
10MWT 
The 10MWT is used to assess walking speed in meters per second (meter/second) over a short 
distance. It can be employed to assess functional mobility, gait, and vestibular function. The 
10MWT can be done in two different ways:  comfortable gait speed, or fast walking speed. A lower 
score indicates worsening.  
The time is measured for the middle 6 m to allow for patient acceleration and deceleration: 
• the time is started when any part of the leading foot crosses the plane of the 2-meter mark; 
• the time is stopped when any part of the leading foot crosses the plane of the 8-meter mark. 
The total time taken to ambulate 6 meters (m) is recorded to the nearest hundredth of a second. 6 
m is then divided by the total time (in seconds) taken to ambulate. If a patient requires total 
assistance or is unable to ambulate at all, a score of 0 m/s should be documented. 
R-ODS 
The R-ODS is a 24-item patient-reported outcome instrument and linearly weighted scale 
developed to measure the activity and social participation limitations in patients with Guillain-
Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and gammopathy-
related polyneuropathy. The response to each dimension is scored as: 0=not possible to perform, 
1=possible but with some difficulty, 2=possible without any difficulty, and lower score indicates 
worsening disability. This method enables the use of sum scores by creating interval scales 
revealing the real difference in ability levels between patients and within patients in time. 
If any of 24 items is missing, then the summed score will be set as missing. 
COMPASS-31 
COMPASS-31 is a 31-item questionnaire that evaluates autonomic function across 6 domains: 
orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor. 
Individual questions within domains inquire about symptom frequency (rarely to almost always), 
symptom severity (mild to severe), and symptom improvement (gotten much worse to completely 
gone).  
Questions include either “yes” or “present” will be scored as 1, “no” or “not present” scored as 0. 
All questions regarding the frequency of symptoms will be scored as 0 points for “rarely” or 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 37 of 38 
“never”, 1 point for “occasionally” or “sometimes”, 2 points for “frequently” or “a lot of the time” 
and 3 points for “almost always” or “constantly”. All questions regarding the severity of symptoms 
will be scored as 1 point for “mild”, 2 points for “moderate”, and 3 points for “severe”. When 
assessing the time course of a symptom, will be scored 0 points for responses of representing 
improvement such as “gotten/getting somewhat better”, “gotten/getting much better”, “completely 
gone” and “I have not had any of these symptoms”, 1 point for “stayed about the same”, 2 points 
for “gotten/getting somewhat worse” and 3 points for “gotten/getting much worse.” The scores for 
changes in bodily functions depended on the individual question asked. For example, “I get full a 
lot more quickly now than I used to when eating a meal” will be scored 2 points, “I get full more 
quickly now than I used to when eating a meal” will be score as 1 point, and “I get full less quickly 
now than I used to”, “I get full a lot less quickly now than I used to” will be scored 0 points, while 
the answer “I sweat somewhat more than I used to”, “I haven’t noticed any changes” will be given 
0 point, “I sweat much more than I used to” and “I sweat somewhat less than I used to” will be 
given 1 point and “I sweat much less than I used to” will be scored 2 points. A detailed list of can 
be found in Table 3 of Appendix 6.3. 
Depending on the domain, possible scores in each domain ranged from 6 (vasomotor) to 28 
(gastrointestinal). Final score is a sum total of all subscales varying from 0 to 100, with higher 
scores indicating worsening of autonomic dysfunction. 
EQ-5D-5L 
EQ-5D-5L is a standardized measure of health status developed by the EuroQoL Group to provide 
a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists 
of the EQ-5D-5L descriptive system and the EQ Visual analog scale (VAS). 
The EQ-5D-5L descriptive system comprises five dimensions (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression). The response to each dimension is scored as follows: 
1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, 5=unable. Lower 
score indicates worsening of QOL. 
The EQ VAS is used as a quantitative measure of health outcome as judged by the individual 
respondent. The EQ VAS records a self-rating of health status on a vertical VAS anchored at 100 
(best imaginable health state) at the top and 0 (worst imaginable health state) at the bottom. 
If any of five dimensions is missing, then the index value will be set as missing. 
PGIC 
PGIC is a single-item scale. Patients choose the response that best describes the overall change in 
their amyloidosis condition since they started taking the study medication. Patients rate their 
change on a 5-point scale as (1) much better, (2) a little better, (3) no change, (4) a little worse, 
(5) much worse. 
If the scale is missing, then PGIC score will be set as missing. 
PGIS 
PGIS is a single-item scale.  Patients choose the response below that best describe the severity of 
the amyloidosis condition over the past week on a 5-point scale: (0) none, (1) mild, (2) moderate, 
(3) severe, or (4) very severe. 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 38 of 39 
If the scale is missing, then PGIS score will be set as missing.  
 
4.10.1.1 Multi-center Study 
This study will be conducted at multiple centers worldwide. For analyses that include investigative 
site, the analysis will use pooled sites.  All sites with fewer than two randomized patients per 
treatment group with non-missing baseline and Week 66 mNIS+7 composite scores will be pooled 
together within the same country and considered as a single site for analysis. If this results in any 
site with fewer than two randomized patients per pooled site, the smallest site will be pooled with 
the next smallest site within the same geographic region (North America, Europe, or South 
America/Australasia/Asia).  If there are no other sites in the region, no further pooling will be 
conducted. 
4.10.1.2 Adjustments for Covariates 
The primary efficacy analysis will be adjusted for the following covariates measured at Baseline: 
- Disease stage (Stage 1/Stage 2) 
- V30M mutation (Yes/No) 
- Previous treatment (Yes/No) 
- Baseline value of endpoint 
4.10.1.3 Handling of Dropouts or Missing Data 
Composite score:  NIS score, modified +7 score, or mNIS+7 score  
Missing data imputation strategies for missing visit level data 
If a patient misses a visit (or the visit is performed outside the analysis visit window), or the entire 
mNIS+7 assessment is not conducted at a visit, then the mNIS+7 and the composite, components 
and subcomponents will be considered as missing at that visit. In a Mixed Model for Repeated 
Measures (MMRM), missing data are not explicitly imputed. Instead, all available post-Baseline 
assessments (within the scheduled visit windows) of the endpoint during the treatment period are 
utilized and via modelling of the within subject correlation structure, the endpoint treatment 
differences (which are adjusted to take account of missing data) are derived. In addition, several 
‘Missing not at random’ methods are described in Section 4.10.3.2 and will be used as sensitivity 
analyses to impute missing visit level data. 
Missing data imputation strategies for missing assessment level data 
Two independent assessments of the primary efficacy endpoint, mNIS+7, are planned at the 
baseline visit and the Week 66 visit, and at the early termination visit (for patients that terminate 
treatment early). A single mNIS+7 assessment is also planned at the Week 35 and Week 85 visit. 
The mean of the two replicate assessments within visit will be used for analysis of both the baseline 
and Week 66 visits (provided both visits fall in the visit window and are within 52 days of the last 
dose of medication). Subcomponent scores will be averaged first. Note, for NIS, an additional step 
is needed by summing left side and right side averaged score to obtain average subcomponent 
scores.   These will be referred to as the averaged subcomponent scores.   
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 41 of 42 
treatment groups) will be used to impute the missing baseline question value.  For post-baseline 
visits during the treatment period, any missing question values will be imputed using the last 
observed or imputed question value (including baseline value). For the symptom domain, in 
the case that a patient responded on a particular question (Questions 1-7) as not a having the 
symptom but also marked presence of the symptom in their feet, legs, hands, or arm, the 
question will be set to missing and the imputation rules will be followed.  
• Otherwise, the total for that domain will be set to missing.  
The Norfolk QOL-DN total score will be calculated by summing the imputed domain scores.  If 
any domain score after imputation is still missing, then the Norfolk QOL-DN total score will be 
set to missing. 
The Norfolk QOL-DN individual domain and total scores will only be calculated for visits where 
the patient had a Norfolk QOL-DN assessment. The individual domain and total scores are set to 
be missing if a patient misses the visit or does not have a Norfolk QOL-DN assessment at that visit.   
NSC Domain and Total score 
Two independent assessments of NSC are planned at the Baseline visit and the Week 66 visit. A 
single NSC assessment is planned at the Week 35 visit. The mean of the two replicate assessments 
within a visit will be used for analysis of both the Baseline and Week 66 visits (provided both visits 
fall in the visit window and are within 52 days of the last dose of medication). The individual 
questions scores will be averaged first. These will be referred to as the averaged question scores.  
At Baseline and Week 66, in the event that only one NSC assessment has been performed, the 
single NSC assessment will be used in place of the mean value for that visit for the averaged 
question score. If both of the NSC assessments are missing, the averaged question score is set to 
missing. At Week 35, only one assessment is performed, therefore the single NSC assessment will 
be used as the averaged question score for that visit. The sub-domain and domain scores will be 
computed using the averaged question scores.  
Imputing Missing Assessment Averaged Question Scores   
The following imputation rule will be applied at the domain level for the sensory (hypo / loss of 
sensation), sensory (paresthesia, hyper sensation), autonomic (GI and urinary incontinence) and 
the autonomic (other than GI/urinary incontinence) domains 
• If at least 50% of the averaged question scores in the domain are available, the missing 
questions will be set to be equal to the mean of the non-missing averaged question scores in 
the domain. The total domain score is then calculated from the sum of the non-missing and 
imputed averaged question scores in the domain. 
• Otherwise, the domain score will be considered to be missing 
Note for the imputation of the autonomic (other than GI/urinary incontinence) component in 
women, questions 35 and 36 are ignored and are not included in the imputation procedure 
The following imputation rule will be applied at the sub-domain level for the four-muscle weakness 
sub-domains (head and neck, chest, upper limb, lower limb): 
• If at least 50% of the averaged question scores in the sub-domain are available, the missing 
averaged question scores will be set to be equal to the mean of the non-missing questions in 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 42 of 43 
the sub-domain. The total sub-domain score is then calculated from the sum of the non-missing 
and imputed averaged question scores in the sub-domain 
• Otherwise, the sub-domain score will be considered to be missing 
The total value for the muscle weakness domain score is calculated by summing the four sub-
domain scores.  If one or more of the sub-domain scores is missing, the muscle weakness domain 
score will be missing. 
The total NSC score is calculated by summing the 5 domain scores.   If one or more of the domain 
scores is missing the total NSC score will be missing. 
Pattern of Missing Data  
For mNIS+7 and Norfolk QOL-DN composite scores, the pattern of missing data will be explored.  
Multiple imputation methods (Section 4.10.3.2) will be used to impute missing data in the 
sensitivity analyses of the primary efficacy endpoint. 
 
Imputation of Missing/Partial Dates  
The imputation of partial or missing dates for adverse events are detailed in Section 4.12.1, and 
prior/concomitant medications Section 4.8. The hATTR-PN /FAC diagnosis and onset date of 
hATTR-PN /FAC symptoms only collected year and month information in CRF. To facilitate the 
calculation of duration, the imputation rules are detailed in Section 4.6. 
Replicated Data, Unscheduled Visits, and Early Termination Visits  
When change from Baseline is assessed, unless otherwise specified, only patients with both 
baseline and post-baseline measurements will be included in the analyses. If baseline or post-
baseline value is missing, then the change from baseline will be set to missing.   
For patients who withdraw, all data will be reported prior to the point of withdrawal in line with 
the population definitions and the specified analysis.   
For data that are scheduled to be measured in duplicate or triplicate, the mean will be presented in 
tables and figures, while all measured values will appear in the listings. 
If more than the scheduled number of measurements is taken, the mean will include all replicate 
measurements.  
4.10.1.4 Data Summary Plan 
The table below details what data will be included in the summary and analysis output by endpoint 
type, and what output is planned for Week 35 interim analysis, Week 66 final analysis, EOT at 
Week 85 and what output will be updated for the EOS. Data summarized/analyzed at 35 Week 
interim, 66 Week final analysis, and EOT will be based on data collected up to the date of the data 
cut. In select instances, the data for a type of endpoint that is summarized or analyzed may not be 
consistent with the rules in the Table; such exceptions will be noted in this SAP. Note: assessments 
for mNIS+7, NSC, and ophthalmology done early in the treatment period that are used for baseline 
cannot also be used as an on-treatment assessment.  
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 45 of 46 
 
 
Week 35 Interim Analysis treatment comparison 
Below are the 2 primary treatment comparisons planned in the interim analysis: 
• Co-Primary Endpoint: Comparison of percent change from Baseline to Week 35 in the 
serum TTR between ION-682884 and NEURO-TTR placebo in the FAS 
• Co-Primary Endpoint: Comparison of change from Baseline to Week 35 in the mNIS+7 
between ION-682884 and NEURO-TTR placebo in the FAS 
If both co-primary endpoints of interim analysis (TTR and mNIS+7) are significant at two-sided 
alpha level of 0.025, then the secondary endpoint (Norfolk) below will be tested at the interim 
analysis at alpha level of 0.025.   
• Secondary Endpoint: Comparison of change from Baseline to Week 35 in the Norfolk 
total score between ION-682884 and NEURO-TTR placebo in the FAS 
 
Week 66 Final Analysis Treatment Comparison 
  
Week 66 Primary Endpoints Analysis 
Below are the 3 primary treatment comparisons planned in the final analysis: 
• Co-Primary Endpoint: Comparison of percent change from Baseline to Week 65 in the serum 
TTR between ION-682884 and NEURO-TTR placebo in the FAS 
• Co-Primary Endpoint: Comparison of change from Baseline to Week 66 in the mNIS+7 
between ION-682884 and NEURO-TTR placebo in the FAS 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 46 of 47 
• Co-Primary Endpoint: Comparison of change from Baseline to Week 66 in the Norfolk total 
score between ION-682884 and NEURO-TTR placebo in the FAS 
In the Week 66 Final Analysis, for those endpoints that were statistically significant at the Week 
35 interim analysis, their corresponding tests at the Week 66 final analysis will not be conducted. 
The non-significant endpoint(s) (e.g., serum TTR and/or mNIS+7) and the co-primary endpoint 
Norfolk will be tested at the final analysis. The alpha level of the final analysis for each endpoint 
will be determined by the resampling procedure (Westfall and Young 1993) as follows. 
Let T1 and T2 be the standardized test statistics at the interim and final analyses, respectively. In 
order to determine the alpha level for the final analysis, the correlation between T1 and T2 is first 
estimated based on the resampling approach: 
• Among the 108 ION-682884 treated patients and 52 NEURO-TTR placebo patients, randomly 
assign 108 patients to the ION-682884 treated group and 52 patients to NEURO-TTR placebo 
group. 
• Apply the re-randomized treatment assignment to the interim data and obtain the standardized 
test statistics T1. 
• Apply the re-randomized treatment assignment to the final data and obtain the standardized test 
statistics T2. 
Repeat the above procedure N times (N = 10000) and obtain N pairs of test statistics T1 and T2. 
The correlation between T1 and T2 will then be estimated as the sample correlation of the N pairs. 
Let c1 be the cut-off point for the interim 2-sided test corresponding to an alpha of 0.025. Once the 
estimated correlation ρ is available, the cut-off point c2 for the final analysis is obtained by solving 
the nonlinear equation Pr(|T1| ≥ c1 or |T2| ≥ c2) = 0.05, where (T1, T2) follow a bivariate normal 
distribution with mean vector (0, 0), standard deviations of 1 and correlation ρ.  See Appendix 6.4 
for the sample programming code for alpha used in the final analysis.   
 
Week 66 Secondary Endpoint Analysis 
If all the co-primary endpoints are significant, the following secondary endpoints, which are not 
planned to be tested in the interim analysis, will be tested in the final analysis at a 2-sided alpha 
level  of 0.05.  The multiplicity will be controlled by using the ranking strategy in the following 
testing sequence: 
• Secondary Endpoint: Comparison of change from Baseline to Week 66 in the NSC between 
ION-682884 and NEURO-TTR placebo in the FAS 
• Secondary Endpoint: Comparison of change from Baseline to Week 35 in the NSC between 
ION-682884 and NEURO-TTR placebo in the FAS 
• Secondary Endpoint: Comparison of change from Baseline in the PCS score of SF-36 at Week 
65 between ION-682884 and NEURO-TTR placebo in the FAS 
• Secondary Endpoint: Week 66 Final Analysis: Comparison of change from Baseline to Week 
65 in the PND between ION-682884 and NEURO-TTR placebo in the FAS 
• Secondary Endpoint: Comparison of change from Baseline to Week 65 in mBMI between ION-
682884 and NEURO-TTR placebo in the FAS 
 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 47 of 48 
4.10.2 Primary Efficacy Variable  
4.10.2.1 Primary Endpoint Analysis at Interim Analysis 
Below are the 2 primary endpoint analyses for interim analysis: 
• Comparison of percent change from Baseline to Week 35 in the serum TTR between ION-
682884 and NEURO-TTR placebo in the FAS 
• Comparison of change from Baseline to Week 35 in the mNIS+7 between ION-682884 and 
NEURO-TTR placebo in the FAS 
The significance level of two-sided 0.025 will be used for both comparisons.   
As noted in the Section 4.10.1, the TTR level from the Placebo arm in the NEURO-TTR trial will 
be converted using the following formula to match data generated by the current assay 
y=0.0057x^2+0.5843x-0.3819.  The converted value will be then used in the primary analysis. 
The percent change in serum TTR from Baseline to Week 35 will be analyzed using the MMRM 
model adjusted by propensity score weights. The MMRM model will also include the effects of 
treatment (ION-682884 or NEURO-TTR placebo), time (categorical), disease stage (Stage 1/Stage 
2), V30M mutation (Yes/No), and previous treatment with Vyndaqel® or Diflunisal (Yes/No), 
treatment-by-time interaction, baseline value of the endpoint, and the baseline-by-time interaction. 
The propensity score will be calculated for each NEURO-TTR placebo or ION-682884 patient 
using a logistic regression model with covariates including disease stage (Stage 1/Stage 2), V30M 
mutation (Yes/No), and previous treatment with Vyndaqel® or Diflunisal (Yes/No). 
Model parameters and treatment effects could be estimated by the following example SAS code: 
 
PROC LOGISTIC data=xxx; 
CLASS trtp distac pretrtc v30ttrc ; 
MODEL trtp (event="ION-682884")=distac pretrtc v30ttrc ; 
OUTPUT out=Propensity_Scores pred=pred; 
run; 
PROC MIXED data=xxx; 
CLASS trtp visit usubjid distac pretrtc v30ttrc;  
MODEL endpoint=trtp distac pretrtc v30ttrc baseline visit visit*baseline visit*trtp / 
DDFM=kr; 
REPEATED visit / SUBJECT=usubjid TYPE=un; 
LSMEANS visit*trtp / CL DIFF; 
Weight wt;  
RUN; 
The ATT (average treatment effect for treated) approach will be used with weight: =1 for subjects 
in the 682884-CS3 treated group; pred/(1-pred) for subjects in the NEURO-TTR placebo control 
group  
In this model, missing data are not explicitly imputed. Instead, all available post-baseline 
assessments up to the Week 35 endpoint during the treatment period (which fall in the visit 
windows) for subjects in the FAS are utilized, and via modelling of the within-subject correlation 
structure, the endpoint treatment differences (which are adjusted to take account of missing data) 
are derived.  The estimation of treatment differences is based upon the assumption that the missing 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
ION-682884-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
 Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019 
 Page 48 of 49 
data follows a missing at random mechanism (i.e., the missingness of the observations may be 
dependent on the observed outcomes or covariates, but not on unobserved outcomes). 
An unstructured variance-covariance matrix will be used to model the within-patient errors, and 
the degrees of freedom will be determined using Kenward-Roger method (Kenward, M. G. and 
Roger, J. H. (1997)).  If there are convergence issues with the model, the six methods below will 
be conducted in the following sequence to solve the convergency issues.   
1) SCORING=4 option could be used in the PROC MIXED statement in SAS.  This will direct
SAS to use the Fisher scoring with the first 4 iterations.
2) TYPE = FA0(t) option will be used where t is the dimension of covariance matrix.
Sample SAS Code:
PROC MIXED data=xxx; 
CLASS trtp visit usubjid distac pretrtc v30ttrc;  
MODEL endpoint=trtp distac pretrtc v30ttrc baseline visit visit*baseline 
visit*trtp / DDFM=kr; 
REPEATED visit / SUBJECT=usubjid TYPE= FA0(t); *where t is the dimension 
of covariance matrix;  
LSMEANS visit*trtp / CL DIFF; 
Weight wt;  
RUN; 
3) A heterogeneous compound symmetry covariance structure (TYPE=csh) will be used
with robust “sandwich” estimator for the standard errors of the fixed effects parameters.
Sample SAS Code:
PROC MIXED data=xxx empirical; 
CLASS trtp visit usubjid distac pretrtc v30ttrc;  
MODEL endpoint=trtp distac pretrtc v30ttrc baseline visit visit*baseline 
visit*trtp / DDFM=kr; 
REPEATED visit / SUBJECT=usubjid TYPE=csh;  
LSMEANS visit*trtp / CL DIFF; 
Weight wt;  
RUN; 
4) A heterogeneous first-order autoregressive AR(1) structure (TYPE=arh(1)) will be used
with robust “sandwich” estimator for the standard errors of the fixed effects parameters.
5) A homogeneous compound symmetry covariance structure (TYPE=cs) will be used with
robust “sandwich” estimator for the standard errors of the fixed effects parameters.
6) A homogeneous first-order autoregressive AR(1) structure (TYPE=ar(1)) will be used
with robust “sandwich” estimator for the standard errors of the fixed effects parameters.
The treatment contrast for each post-baseline visit up to Week 35 will be estimated by the model, 
with the Week 35 estimate considered the primary for the interim analysis. The normality 
assumptions for the MMRM models will be formally tested using a Shapiro-Wilks test at the 0.01 
significance level and assessed by inspection of the following plots: 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 49 of 50 
• Histogram of marginal studentized residuals derived from the MMRM model. 
• Normal probability plot. 
If the Shapiro-Wilks test assessing normality of the MMRM residuals is statistically significant at 
the 0.01 level, a stratified Wilcoxon rank sum test will be provided and the result will be considered 
as Primary Analysis for TTR.  
The mNIS+7 is scheduled to be assessed at Week 35, Week 66, and Week 85. 
Because only 1 post-Baseline assessment (Week 35) is available at Week 35 Interim Analysis, 
the treatment comparison at Week 35 will be based on the analysis of covariance (ANCOVA) 
model adjusted by propensity score.  The Analysis of covariance (ANCOVA) model will also 
include the effects of treatment (ION 682884 or NEURO-TTR placebo), disease stage (Stage 
1/Stage 2), V30M mutation (Yes/No), and previous treatment with Vyndaqel® or Diflunisal 
(Yes/No), and the baseline value of the endpoint. Patients with a missing mNIS+7 at Week 35 
will have value multiple imputed using an imputation model (Based on MAR assumption) that 
contains the following variables: disease stage (Stage 1/Stage 2), V30M mutation (Yes/No), 
previous treatment with Vyndaqel® or Diflunisal (Yes/No), and the Baseline value of the 
endpoint and the multiple imputation will be stratified by treatment group (Schafer 1997; Schafer 
1999).  The details are provided in Section 4.10.3.2. Of note, multiple imputation here is treated 
as primary analysis, which will be based on on-treatment data for Full Analysis Set. In addition, 
ANCOVA based on observed data (with missing value) will be treated as sensitivity analysis 
(please see Sensitivity Analysis 8).   
Similarly to MMRM above, if the Shapiro-Wilks test assessing normality of the ANCOVA 
residuals is statistically significant at the 0.01 level, a stratified Wilcoxon rank sum test will be 
provided.  
4.10.2.2 Secondary Endpoint Analysis at Interim Analysis 
If both co-primary endpoints of interim analysis (TTR and mNIS+7) are significant at alpha level 
of two-sided 0.025, then the secondary endpoint (Norfolk) below will be tested at the interim 
analysis at alpha level of 0.025.   
• Secondary Endpoint: Comparison of change from Baseline to Week 35 in the Norfolk total 
score between ION-682884 and NEURO-TTR placebo in the Full Analysis Set 
Similarly to mNIS+7, because only 1 post-Baseline Norfolk assessment (Week 35) is available at 
Week 35 interim analysis, the same analysis of mNIS+7 will be applied for Norfolk.   
 
4.10.2.3 Primary Analysis at Week 66 Final Analysis 
Below are the 3 primary treatment comparisons planned in the Week 66 final analysis: 
• Co-Primary Endpoint: Comparison of percent change from Baseline to Week 65 in the serum 
TTR between ION-682884 and NEURO-TTR placebo in the FAS 
• Co-Primary Endpoint: Comparison of change from Baseline to Week 66 in the mNIS+7 
between ION-682884 and NEURO-TTR placebo in the FAS 
• Co-Primary Endpoint: Comparison of change from Baseline to Week 66 in the Norfolk total 
score between ION-682884 and NEURO-TTR placebo in the FAS 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 50 of 51 
In the Week 66 Final Analysis, for those statistically significant endpoints at the Week 35 interim 
analysis, their corresponding tests at the Week 66 final analysis will not be conducted. The non-
significant endpoint(s) (serum TTR and/or mNIS+7) and the co-primary endpoint Norfolk will be 
tested at the final analysis. The alpha level of the final analysis for each endpoint will be determined 
by the resampling procedure (see Section 4.10.1.5).  
For percent change from Baseline of TTR at Week 65, change from Baseline of mNIS+7 at Week 
66, and change from Baseline of Norfolk QOL-DN at Week 66, a MMRM model adjusted by 
propensity score weights will be used. Similar to the interim analysis for TTR, the MMRM model 
will include the effects of treatment (ION-682884 or NEURO-TTR placebo), time (categorical), 
disease stage (Stage 1/Stage 2), V30M mutation (Yes/No), and previous treatment with Vyndaqel® 
or Diflunisal (Yes/No), treatment-by-time interaction, baseline value of the endpoint, and the 
baseline-by-time interaction. The propensity score will be calculated using the same logistic 
regression model in the primary analysis (Section 4.10.2.1). In this model, missing data are not 
explicitly imputed. Instead, all available post-baseline assessments up to the Week 65 (or Week 
66) endpoints during the treatment period (which fall in the visit windows) for subjects in the FAS 
are utilized and via modeling of the within subject correlation structure, the endpoint treatment 
differences (which are adjusted to take account of missing data) are derived. 
 
4.10.3 Additional Analyses of Primary Endpoints 
4.10.3.1 Sensitivity Analyses 
In addition to the primary efficacy analysis performed in either interim analysis or final analysis, 
the following sensitivity analyses will be conducted on the FAS and for each endpoint (TTR, 
mNIS+7, Norfolk) performed in the Week 35 interim analysis and Week 66 final analyses, except 
where noted: 
• Sensitivity Analysis 1 (Non-Parametric Analysis).  The non-parametric stratified Wilcoxon 
rank sum test will also be performed for the primary study endpoints adjusted by stratified 
propensity score weights as the sensitivity analysis.  The stratum will consist of 4 quartiles 
levels of the propensity scores (<=Q1, >Q1 and <= Median, > Median and <=Q3, > Q3). 
Hodges-Lehmann estimates of the differences between ION-682884 group and NEURO-TTR 
placebo group based on the Wilcoxon Rank Sum Test will also be provided. The propensity 
score will be calculated using the same logistic regression model in the primary analysis 
(Section 4.10.2.1). This sensitivity analysis will be applied for each analysis (TTR, mNIS+7, 
Norfolk) performed in the Week 35 interim analysis and Week 66 final analyses. 
 
Sensitivity analyses will be performed to investigate the impact of alternative missing data 
assumptions (Multiple imputation, see Section 4.10.3.2). All assessments that are within the 
analysis windows are included, even if conducted more than 52 days after last dose. These 
sensitivity analyses will be applied for serum TTR in the Week 35 interim analysis and serum TTR, 
mNIS+7, and Norfolk in Week 66 final analyses. These analyses will be done on the Safety Set 
and will be labeled as: 
o Sensitivity Analysis 2 – Multiple Imputation assuming Missing at Random (MAR) 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 51 of 52 
o Sensitivity Analysis 3 – Multiple Imputation assuming Copy Increments from Reference 
(CIR) 
o Sensitivity Analysis 4 – Multiple Imputation assuming Jump to Reference (J2R) 
 
• Sensitivity Analysis 5 (PPS) – The primary efficacy analysis will be repeated, using the PPS 
population. This sensitivity analysis will be applied for each analysis (serum TTR, mNIS+7, 
Norfolk) performed in the Week 35 interim analysis and Week 66 final analyses. 
• Sensitivity Analysis 6 (Responder Analysis) – A responder analysis based on the change in 
mNIS +7 score will be conducted to examine whether improvement in response is consistent 
over a range of response thresholds. A responder is defined as a patient whose mNIS +7 score 
change from baseline to Week 66 is less than or equal to the threshold value. Thresholds that 
will be tested will include -2, 0, 2, 4, 6, 8, 10 points above the baseline value.  For each of these 
specific response thresholds, the response rates at Week 66 for both the ION-682884 treated 
group and the NEURO-TTR placebo group will be calculated and plotted against the response 
threshold.  Patients that terminate treatment early irrespective of the reason or that had missing 
Week 66 data will be considered a non-responder.  
This sensitivity analysis will also be applied for mNIS+7 performed in the Week 35 interim 
analysis using change from baseline to Week 35. 
Same responder analysis will also be presented for Norfolk for both Week 35 interim analysis 
and Week 66 final analysis. 
  
• Sensitivity 
Analysis 
7 
(Propensity 
Analysis 
using 
6 
covariates). 
Additional 
ANCOVA/MMRM model will also be performed for the primary endpoints adjusted by 
propensity score weights as the sensitivity analysis.  In addition to 3 factors (Disease Stage, 
V30M, and Previous treatment) used in the logistic model for propensity score in the primary 
analysis, this sensitivity analysis will include additional 3 covariates (6 covariates total) below: 
o Gender (Male, Female) 
o Modified BMI baseline (continuous value) 
o Region (Europe, North America, South America/Australia/Asia) 
  
• Sensitivity Analysis 8 (Observed data - ANCOVA) - The same ANCOVA in the primary 
analysis will be performed based on observed data for mNIS+7 and NORFOLK for Week 35 
Interim analysis.  
 
4.10.3.2 Multiple Imputation Methodology 
First, a repeated measures Gaussian model will be fitted to the data using a Bayesian approach, 
with non-informative priors for the mean and variance-covariance matrix to provide a joint 
posterior for the parameters in this model.  The repeated measures Gaussian model will include 
separate mean profiles for each treatment group and the same covariates as those in the primary 
MMRM analysis for final analysis and TTR at interim analysis based on on-study data for Safety 
Set.  
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 52 of 53 
For mNIS+7 and NORFOLK at interim analysis, the same ANCOVA model used in the primary 
analysis will be used in multiple imputation based on on-treatment data for Full Analysis Set.   
Independent samples will then be drawn from the posterior distributions for the mean and variance-
covariance matrix to provide inputs into an imputation model.  For each subject with missing data, 
these sampled values of the parameters for mean vectors and the variance- covariance matrices 
specify a joint distribution for their observed and unobserved outcome data. 
The post-withdrawal part of each pattern-specific distribution will be modelled using three 
different approaches discussed below.  This imputation model will have the same covariates as 
those in the primary MMRM analysis. 
Based on this imputation model, a single set of data will be sampled for the missing data based on 
the distribution for the subject’s missing data conditional upon their observed data. 
The post-withdrawal part of each pattern-specific distribution will be modelled using these three 
approaches: 
1. MAR approach.  
The means and variance-covariances following withdrawal are chosen to reflect the subject’s own 
treatment group. This approach should provide similar numerical results to the primary analysis. 
For Final analysis and TTR at Week 35 interim analysis, all assessments that are within the analysis 
windows are included in this analysis, even if conducted more than 52 days after last dose (On-
Study). For mNIS+7 and NORFOLK at Week 35 interim analysis, only data within 52 days after 
last dose (On-Treatment) will be included. 
2. CIR approach.  
The CIR approach is detailed in Carpenter et al. (2013) and addresses a potential pattern of 
informative missingness where the assumption is that the active Study Drug halts or slow disease 
progression, and the disease progresses after treatment is discontinued. In CIR, missing data in the 
NEURO-TTR placebo group will be imputed under a within-treatment arm MAR assumption. For 
patients in the 682884-CS3 treatment group (ION-682884), their mean profile (i.e., mean 
increments) will track that of the NEURO-TTR placebo group, but starting from the benefit 
obtained from the previous visit. All assessments that are within the analysis windows are included 
in this analysis, even if conducted more than 52 days after last dose.   
3. J2R approach. 
The J2R approach is detailed in Carpenter et al. (2013) and is an extremely conservative imputation 
approach that assumes that a patient receiving active Study Drug does not sustain benefit after 
discontinuation of study drug. In J2R, missing data in the NEURO-TTR placebo group will be 
imputed under a within-treatment arm MAR assumption. For patients with missing data in the 
ION-682884 treatment group, their mean response distribution is set to equal that of the NEURO-
TTR placebo group. All assessments that are within the analysis windows are included in this 
analysis, even if conducted more than 52 days after last dose. 
For each imputation method used, at least 500 imputed datasets will be generated. The imputed 
observations in each dataset will be checked to ensure they are within the possible change from 
baseline range for the particular subject they belong to. If a dataset contains out-of-range values, it 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 53 of 54 
will be discarded and a new dataset will be generated until there are 500 datasets which contain no 
out-of-range values. Each of 500 imputed data sets will then be analyzed using a simple ANCOVA 
model at Week 35 and Week 66, and the resulting treatment differences and their standard errors 
will be combined using Rubin’s rules. The ANCOVA model adjusted by propensity score will 
include the effects of treatment (ION 682884 or NEURO-TTR placebo), disease stage (Stage 
1/Stage 2), V30M mutation (Yes/No), and previous treatment with Vyndaqel® or Diflunisal 
(Yes/No), and the baseline value of the endpoint.  Note that in these analyses, efficacy assessments 
that are within the analysis window but more than 52 days after last dose will be included. This is 
different from the primary analysis, where data after 52 days from last dose is excluded. The 
number of imputed datasets may be increased after review of results if the simulation error is 
considered large.  
A random seed to be used by a random number generator with value of 2855 will be used to initiate 
data imputation for all three methods. 
4.10.4 Subgroup Analyses of Primary Endpoints 
Subgroup analyses will be conducted for each of the two primary efficacy endpoints in the FAS.  
Subgroups defined by the following variables will be evaluated: 
• V30M mutation (Yes, No) 
• Age (< 65 years, 65-74 years, ≥ 75 years old) 
• Race (White, non-White) 
• Sex (Male, Female) 
• Region (North America, Europe, South America/Australia/Asia)  
• Previous treatment with Vyndaqel® or Diflunisal (Yes, No) 
• Disease stage (Stage 1, Stage 2) 
• FAC Clinical Diagnosis from CRF (Yes, No) 
• CM subgroup (Yes, No): CM subgroup (Yes) includes patients with 1) a diagnosis of TTR 
cardiomyopathy at study entry or 2) baseline interventricular septum thickness >= 13 mm on 
echocardiogram AND no hypertension or ventricular hypertrophy in past medical history or 
diagnosed on study AND no two consecutive systolic blood pressure readings of >=150 mmHg 
at any time during the study (including screening and baseline visits).     
For TTR (at Week 35 and Week 65), mNIS+7 (at Week 66) and Norfolk (at Week 66), the MMRM 
adjusted by propensity score for the change from baseline with include fixed categorical effects for 
treatment, time, disease stage, V30M mutation, and previous treatment, treatment-by-time 
interaction, treatment-by-subgroup interaction, and treatment-by-time-by-subgroup interaction.  
The baseline value of the endpoint and the baseline-by-time interaction will be included as 
covariates in the model. The treatment-by-subgroup interaction at each timepoint will be tested at 
the significance level of 0.10. Treatment group differences will be evaluated within each category 
of the subgroup, regardless of whether the interaction is statistically significant.  The propensity 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 54 of 55 
score will be calculated using the same logistic regression model in the primary analysis 
(Section 4.10.2.1).   
For mNIS+7 and Norfolk at Week 35, the ANCOVA adjusted by propensity score for the change 
from baseline with include fixed categorical effects for treatment, disease stage, V30M mutation, 
and previous treatment with Vyndaqel® or Diflunisal.  The baseline value of the endpoint will be 
included as covariates in the model. The treatment-by-subgroup interaction will be tested at the 
significance level of 0.10. Treatment group differences will be evaluated within each category of 
the subgroup, regardless of whether the interaction is statistically significant.  The propensity score 
will be calculated using the same logistic regression model in the primary analysis 
(Section 4.10.2.1).  
4.10.5 Secondary Efficacy Variables for Week 66 Final Analysis 
The secondary endpoints at Week 66 Final Analysis include the following analyses: 
• Comparison of change from Baseline to Week 66 in the NSC between ION-682884 and 
NEURO-TTR placebo in the FAS 
• Comparison of change from Baseline to Week 35 in the NSC between ION-682884 and 
NEURO-TTR placebo in the FAS 
• Comparison of change from Baseline in the PCS score of SF-36 at Week 65 between ION-
682884 or NEURO-TTR placebo in the FAS 
• Comparison of change from Baseline to Week 65 in the PND between ION-682884 and 
NEURO-TTR placebo in the FAS  
•  Comparison of change from Baseline to Week 65 in mBMI between ION-682884 and 
NEURO-TTR placebo in the FAS 
Treatment group differences will be evaluated using the same method as the primary efficacy 
analysis (MMRM described in Section 4.10.2). These analyses will be conducted on both the FAS 
and the PPS populations. No sensitivity analyses will be conducted.   
The normality assumptions for the MMRM will be assessed for each of the secondary endpoints 
by inspecting the following plots: 
• Histogram of marginal studentized residuals derived from the MMRM model. 
• Normal probability plot. 
The non-parametric stratified Wilcoxon rank sum test may be performed as a sensitivity analysis, 
if deemed necessary.  Hodges-Lehmann estimates of the differences between ION-682884 and 
NEURO-TTR placebo as well as distribution-free confidence intervals based on the Wilcoxon 
Rank Sum Test will also be provided.  
 
4.10.6 Pharmacodynamic Analysis 
Analyses of PD endpoints will be evaluated using the same method as the primary efficacy analysis 
(MMRM described in Section 4.10.2).  No sensitivity analyses will be conducted except for TTR.  
All PD analyses will be conducted on both the FAS and the PPS. 
Additionally, the proportion of subjects with percentage decrease from baseline in serum  TTR 
<50%, ≥50%, ≥60%, ≥70%, ≥80%, and ≥90% will be summarized by treatment group at each visit. 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 55 of 56 
 
4.10.7 Exploratory Analyses 
Exploratory analyses include the comparisons of change from Baseline in the following parameters: 
• mNIS+7 
• Norfolk QOL-DN 
• 10MWT 
• R-ODS  
• COMPASS-31 
• EQ-5D-5L 
For mNIS+7 and Norfolk QOL-DN, descriptive statistics will be provided for absolute values and 
change from baseline at Week 85.  
For 10MWT, R-ODS, COMPASS-31 and EQ-5D-5L, descriptive statistics will be provided for 
absolute values and change from baseline at Week 37 and Week 81.  
For PGIC and PGIS, descriptive statistics will be provided for absolute values and change from 
baseline at Week 37 and Week 81.  
 
Exploratory analyses to evaluate the efficacy of ION-682884 as compared to NEURO-TTR 
placebo are listed below: 
• SF-36 components 
• All cause hospitalizations  
• Transthoracic ECHO parameters of interest 
• NT-proBNP 
For SF-36, descriptive statistics will be provided for absolute values and change from baseline at 
Week 35 for each component.  
For NT-proBNP and High-Sensitivity Troponin T, descriptive statistics for original scale and log-
transformed will be provided for absolute values and change from baseline at Week 35 and 65. 
The change from baseline will be analyzed using an ANCOVA model with fixed effects of 
treatment, disease stage (Stage 1/Stage 2), V30M mutation (Yes/No), and previous treatment with 
Vyndaqel® or Diflunisal (Yes/No), and baseline value as covariate based on FAS adjusted by 
propensity score.  The propensity score will be calculated using the same logistic regression model 
in the primary analysis (See Section 4.10.2.1).  
For all cause hospitalizations and all cause hospitalizations in patients with cardiac involvement, 
summary tables will be provided and Chi-square test will be used for analysis. 
Protocol-specified ECHO parameters will be analyzed for patients with baseline wall thickness 
>15mm using an MMRM model with fixed effects of treatment, disease stage (Stage 1/Stage 2), 
V30M mutation (Yes/No), and previous treatment with Vyndaqel® or Diflunisal (Yes/No), and 
baseline value as covariate. 
 
In addition, TTR will be summarized for Inotersen reference arm in 682884-CS3. 
 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 56 of 57 
4.11 PK and IM Analysis 
4.11.1 PK Analysis 
4.11.1.1 Plasma Concentration Data 
Plasma concentrations of ION-682884 (as total full-length oligonucleotides, including fully, 
partially, and un-conjugated ION-682884) or inotersen, along with the scheduled (nominal) and 
actual sampling times (i.e., time from SC dosing) will be listed for each evaluable patient by 
treatment, actual dose, gender, subject IM status, and study day.  Plasma concentrations below the 
lower limit of quantification (LLOQ) will be indicated by “BLQ”.  Percent differences between 
nominal and actual dose, as well as between scheduled and actual sampling times, will also be 
listed for all patients.   
For all patients who receive ION-682884 and/or inotersen treatment, ION-682884 or inotersen 
plasma trough and post-treatment concentrations will be summarized using descriptive statistics 
by treatment, dose, study day, and scheduled time point, without and with stratification by subject 
IM status (see Section 4.11.3).  ION-682884 or inotersen plasma concentrations from the PK 
subgroup will also be similarly summarized.  For the purpose of calculating typical summary 
descriptive statistics (n, mean, SD, SE, %CV, geometric mean, geometric %CV, median, minimum, 
and maximum) for plasma concentrations, all BLQ values will be set to zero. Mean plasma 
concentrations that are below the LLOQ will be presented as BLQ, and the SD, SE, %CV, and 
geometric %CV will be reported as not applicable.  Other stratifications may also be performed if 
deemed warranted to properly interpret the pharmacokinetic analysis. Samples will 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 all evaluable patients, ION-682884 or inotersen plasma trough (pre-dose) and post-treatment 
concentrations versus time (actual) profiles from Study Day 1 up to 729 for each individual patient, 
as well as corresponding mean (+SD) plasma concentration versus time (scheduled) profiles will 
be presented graphically on linear and semilogarithmic scales, without and with stratification by 
subject immunogenicity status (see Section 4.11.3). For the PK subgroup only, ION-682884 or 
inotersen plasma concentration versus time (actual) profiles from Study Day 1, from Study Day 
225, and from Study Day 449, for each patient, as well as corresponding mean (+SD) plasma 
concentration versus time (scheduled) profiles (by treatment), will be presented graphically on 
linear and semilogarithmic scales, without and with stratification by subject immunogenicity status 
(see Section 4.11.3). Other stratifications may also be performed if deemed warranted.  At the 
discretion of the pharmacokineticist and/or biostatistician, samples may be excluded from the mean 
plots if there are large deviations between scheduled and actual sampling times, or large deviations 
between actual dose and nominal dose. 
4.11.2 Plasma PK Parameters 
Non-compartmental PK analysis of ION-682884 or inotersen will be carried out on each evaluable 
individual patient data for the PK subgroup following ION-682884 or inotersen treatment, 
respectively, using Phoenix WinNonlin version 8.3 or higher (Pharsight Corporation, Mountain 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 57 of 58 
View, CA) to determine plasma PK parameters.  For calculation of PK parameters, all BLQ values 
will be set to zero.   
For the PK subgroup only, the following plasma PK parameters will be calculated (when applicable 
and possible) based on actual sampling times: 
• Cmax (µg/mL):  the maximum observed drug concentration in plasma.  Calculated for dosing 
on Study Days 1, 225, and 449. 
• tmax (h): the time at which Cmax occurs.  Calculated for dosing on Study Days 1, 225, and 
449. 
• AUC0-6h (µg•hr/mL):  areas under the plasma concentration-time curve from zero time (pre-
dose) to 6 hours after the SC administration will be calculated using the linear-up log-down 
trapezoidal rule following dosing on Study Days 1, 225, and 449.  
For all evaluable patients (including subjects participating in the PK subgroup) who have sufficient 
post-treatment samples collected, the apparent plasma terminal elimination half-life will be 
calculated as described below:  
• t½λz (day):  the plasma disposition half-life associated with the apparent terminal elimination 
phase may be calculated from the equation, t1/2λz = 0.693/λz, based on any evaluable post-
treatment data with scheduled collections between Days 589 and 729.  A minimum of three 
data points in the elimination phase will be used to define λz, and the correlation of 
determination values (r2_adjusted) have to be at or greater than 0.8 and a span of at least 1.5 
for the estimate to be accepted.  Note: if quantifiable data is only available from just 2 time 
points, span< 1.5, or r2_adjusted < 0.8, this parameter may still be determined at the discretion 
of the pharmacokineticist and will be flagged as such. Note: calculation of this parameter may 
not be possible in patients rolling into an open-label extension study. 
Plasma PK parameters will be listed by treatment, dose, subject ID, subject IM status, and study 
day; and appropriately summarized (overall and separately for the PK subgroup) using descriptive 
statistics (n, mean, SD, SE, %CV, geometric mean, geometric %CV, median, minimum, and 
maximum) by treatment and study day. Additionally, subject IM status stratified (see 
Section 4.11.3) plasma PK parameters will be similarly summarized). Other stratifications may 
also be performed if deemed warranted at the discretion of the pharmacokineticist and/or 
biostatistician. 
Exposure-response relationships between selected pharmacodynamic (including but not limited to 
TTR level, mNIS+7 and Norfolk QOL-DN score) and/or safety measures ((including but not 
limited to ALT) and PK measures (including but not limited to plasma trough concentrations) at 
selected time points (e.g., Day 29, Day 85, Day 225, etc.) may also be explored (may include with 
and without stratification by IM status), where appropriate. 
 
4.11.3 IM Analysis 
Samples collected at pre-dose on Study Days 1 (baseline), 29, 85, 225, 337, 449, 589 and 729, 
including early termination samples for IM assessment will be analyzed for anti-ION-682884 
antibodies or anti-inotersen antibodies (ADA) for patients receiving ION-682884 or inotersen, 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 58 of 59 
respectively.  After the patients switch to ION-682884 treatment, their samples will be analyzed 
for both anti-ION-682884 and anti-inotersen antibodies. 
 
4.11.3.1 Sample Level ADA Data 
An evaluable sample will be designated ‘IM positive’ based on both positive screening and 
confirmation assay results (i.e., confirmed positive result), and otherwise will be deemed ‘IM 
negative’. An unevaluable sample, for example, a sample not being stored properly, or insufficient 
volume for analysis,  will be reported as “unknown”.  Sample IM results (screen positive/negative, 
confirmed positive/negative or unknown, and when applicable, titer of anti-ION-682884 or anti-
inotersen antibodies) before, during, and after treatment with study drug (sample IM 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. 
4.11.3.2 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.   
Furthermore, subjects with positive overall ADA status will 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: sum of treatment-induced ADA and treatment-boosted ADA 
as described below: 
o Treatment-Induced ADA: ADA developed de novo (seroconversion) following 
biologic 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 biologic drug administration (i.e., any time after the initial drug 
administration the ADA titer is greater than the baseline titer by a factor of 8-fold 
or more 
• Treatment-Unaffected ADA: pre-existing ADA that were not affected (boosted) following 
biologic drug administration (i.e., any time after the initial drug administration the ADA 
titer is 4-fold or less) 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 59 of 60 
• ADATYPE would be not applicable (NA) if the subject overall ADA status is negative. 
 
Other subject level IM parameters to be calculated/defined may include but not limited to: 
• 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 confirmed negative; "Unknown" if the 
subject has Week 1 Day 1 pre-dose sample (baseline) unevaluable. 
• Onset of ADA (TFSTADA): i.e., the first day ADA positive sample observed, will be 
calculated by: the date of first sample has “positive” sample IM status - first dose date +1.  
This parameter will be calculated for subjects with positive ADA status overall and subjects 
with treatment-induced ADA, respectively. 
• Last Positive ADA Study Day (TLSTADA): defined as the last positive ADA sample 
observed from the start of study drug treatment and will be calculated by: the date of last 
sample has “positive” sample IM status - first dose date +1 
• Last IM Sampling Study Day (TLSTSAMP): defined as the last ADA sample collected 
from the start of study drug treatment and will be calculated by: the date of last sample 
collected - first dose date +1 
• 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. 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 60 of 61 
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 number and the proportion (percent) of the study 
population during the study period by treatment and dose.  Subject level IM parameters (as 
described above) 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.  Additionally, Subject level IM parameters will be also summarized 
for subjects with Treatment-Induced ADA only (i.e., excluding subjects with pre-existing ADA). 
 
4.11.3.3 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 parameters, 
plasma trough and post-treatment ION-682884 and inotersen concentrations, PD biomarker levels, 
selected clinical efficacy endpoints and safety measures by subject ADA status and titer quartiles, 
summarized using typical descriptive statistics, and presented graphically and/or in tables.  
Efficacy measures to be stratified by subject ADA status will include but may not be limited to 
TTR level, mNIS+7 and Norfolk QOL-DN scores.  Safety measures to be stratified by subject 
ADA status will include but may not be limited to AEs, and lab tests for hematology, liver and 
kidney functions.   
Additionally, within subject comparisons on plasma Cmax and AUC may be conducted in patients 
from the PK subgroup and presented graphically by subject ADA status and treatment if deemed 
appropriate (Wang YM, et al, 2016).   
Lastly, other stratifications (e.g., based on antibody titer, onset of ADA, subjects with treatment-
emergent ADA vs. treatment-unaffected ADA 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. 
 
4.12 Safety Evaluation 
All safety summaries will be based upon the SS per the treatment group below:  
- 
NEURO-TTR Placebo 
- 
NEURO-TTR Inotersen 
- 
ION-682884 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 61 of 62 
- 
Inotersen/ION-682884 prior to switch to ION-682884  
- 
Inotersen/ION-682884 after switch to ION-682884 
 
Additional treatment group (e.g., Inotersen/ION-682884 Total) will be included if applicable. The 
following imputation rules will be applied to impute AE start dates under conservative principles. 
If the month, year, and day are missing, the adverse event start date will be imputed as the treatment 
start date. If month and day are missing and year is available and is the same year as in treatment 
start date, the month and day from the treatment start date will be used to impute the missing month 
and day for the adverse event start date. Otherwise, missing month and day will be imputed as 
January 01. If day is missing and month and year is available and the month and year are the same 
month and year in treatment start date, the day from the treatment start date will be used to impute 
missing day for the adverse event start date. Otherwise, missing day will be imputed as 01. 
4.12.1 Adverse Events 
Adverse events will be coded using the MedDRA Version 25.0 or later version. 
Treatment emergent adverse events (TEAE) are defined as adverse events that occurred or 
worsened after the first dose. An AE with a completely missing start date will be assumed to be 
treatment emergent. Note, Scenario 1 below indicates the ‘worsened’ case. 
In addition, if severity of an AE changes during the study, a separate AE will be recorded for each 
severity on the AE CRF with link. The “first” and “second” AE will be identified based on the AE 
start date and AE end date. The AE start date of the second record is the AE end date of the first 
record. 
These 
linked 
events 
should 
be 
compared 
pairwise 
based 
on 
severity 
(mild/moderate/severe). Consider three scenarios: 
• 
Scenario 1: The first AE record occurs prior to the first dose, the second AE record occurs 
on or after the first dose, and the severity increases: Only the second record will be counted 
as treatment-emergent.  
• 
Scenario 2: The first AE record occurs prior to the first dose, the second AE record occurs 
on or after the first dose, and the severity decreases: Neither record will be counted as 
treatment-emergent. 
• 
Scenario 3: Both records occur on or after the first dose: only the most severe AE will be 
counted as TEAE. 
For 682884-CS3 Inotersen/ION-682884 group, TEAEs which first occurred or worsened on or 
after first dosing date of ION-682884 will be defined as the TEAEs after switch to ION-682884; 
otherwise, they will be defined as TEAEs before switch to ION-682884. 
  
The following imputation rules will be applied to impute AE start dates under conservative 
principles. If the month, year, and day are missing, the adverse event start date will be imputed as 
the treatment start date. If month and day are missing and year is available and is the same year as 
in treatment start date, the month and day from the treatment start date will be used to impute the 
missing month and day for the adverse event start date. Otherwise, missing month and day will be 
imputed as January 01. If day is missing and month and year is available and the month and year 
are the same month and year in treatment start date, the day from the treatment start date will be 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 62 of 63 
used to impute missing day for the adverse event start date. Otherwise, missing day will be imputed 
as 01. If imputed start date is later than end date (not missing or partial missing), start date will be 
imputed using end date.  
The following summaries will be provided for TEAEs by treatment group: 
- An overview of all TEAEs  
- A summary table of TEAEs by SOC and PT 
-  A summary table of TEAEs reported in ≥ 2% of patients (after rounding) in ION-682884 or 
Inotersen treated group (and greater than placebo group) by SOC and PT 
- A summary table of drug-related TEAEs by SOC and PT 
- A summary table of drug-related serious TEAEs by SOC and PT 
- A summary table of TEAEs by maximum severity, SOC and PT 
- A summary table of TEAEs leading to discontinuation of study drug by SOC and PT 
- A summary table of SAEs leading to discontinuation of study drug by SOC and PT  
- A summary table of TEAEs by time from first dose to event onset (< 6 months, ≥ 6 months to 
< 12 months, ≥ 12 months), SOC and PT 
- A summary of death, by SOC and PT 
  
TEAEs will be summarized by subgroups below:   
• Age at CS3 screening (<65 years, 65-74 years, >=75), 
• Sex (Female and Male),  
• Race (White, non-White), 
• Region (North America, Europe, and South America/Australasia/Asia),  
• V30M TTR mutation (Yes, No),  
• Previous treatment with Vyndaqel® or Diflunisal (Yes, No),  
• Disease stage (Stage 1 and Stage 2), 
• FAC Clinical Diagnosis from CRF (Yes, No), 
• CM subgroup (Yes, No) as defined in Section 4.10.4     
Results will not be provided for a variable if the overwhelming majority of patients are within one 
level of the subgroup.  
Adverse events in the following categories will be summarized separately: 
• Adverse events of special interest 
• Other adverse events of interest 
• Injection site reaction (ISR) and Local cutaneous reactions at injection site (LCRIS) 
• Flu-like reactions  
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 63 of 64 
Incidence rate and event rate per 100 patient years of exposure will be presented by PT and SOC 
for the following events:  
• All TEAEs 
• Serious TEAE 
• TEAE with Severity of Severe 
• TEAEs leading to discontinuation of study drug 
• Injection site reaction (ISR) and Local cutaneous reactions at injection site (LCRIS) 
 
Incidence rate and event rate per 100 patient years of exposure will be presented by category and 
preferred term for the following events as well:  
• Adverse events of special interest 
• Other adverse events of interest 
• Flu-like reactions  
 
The formula for Incidence/event rate per 100 patient years of exposure is as below: 
• Total exposure for each patient = [complete/discontinuation date or data cutoff date) - the 
first dose of study drug +1] / 365.25  
• Total exposure across all subjects will be the summation of total exposure for each 
patient.   
• Incidence rate per 100 patient years of exposure = (number of subjects with TEAEs /total 
exposure across all subjects) *100.   
• Event rate per 100 patient years of exposure = (number of TEAEs /total exposure across 
all subjects) *100. 
 
4.12.1.1 Adverse Events of Special Interest (AESI) 
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 could be appropriate. AESI, if defined in the 
study protocol, are required to be reported by the Investigator to the Sponsor immediately, no more 
than 24 hours of the Investigator’s first knowledge of the event. They are not necessarily those 
expected to be related to study drug or those most frequently occurring.  
AESI defined in this SAP are shown in the table below.  Additionally, thrombocytopenia AESI of 
platelet count < 50 x 10^9/L accompanied by a clinically relevant, bleeding events (MB) or 
clinically relevant, non-major bleeding events (CRNMB), or platelet count of < 25 x 10^9/L 
independent of a MB or CRNMB event was defined in the protocol as reportable AESI and should 
be subject to 15-day expedited reporting by the Sponsor to the regulatory agencies. 
 
 
 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 66 of 67 
4.12.1.3  Injection Site Reaction (ISR) and Local Cutaneous Reactions at Injection Site (LCRIS) 
Injection Site Reaction (ISR) defined as TEAEs with MedDRA preferred terms contains text 
“Injection site”. ISR will be summarized by SOC and PT. In addition, ISR will be summarized 
by SOC, PT and injection location which is the location of the last injection prior to AE onset.  
The following MedDRA preferred terms are determined by the Sponsor’s Pharmacovigilance 
personnel to represent the Local Cutaneous Reactions at Injection Site (LCRIS): 
• Injection site erythema 
• Injection site swelling  
• Injection site pruritus 
• Injection site pain 
• Injection site tenderness 
Events that start on the day of injection and persist 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 the injection, 
will be included.  Events with onset date on the day of injection and missing resolution date will 
also be included. 
LCRIS will be summarized by SOC and PT.   
Percentage of injections leading to LCRIS will also be summarized.  Percentage of injections 
leading LCRIS will be calculated for each patient as (A/B)*100, where A is the number of 
injections with a local cutaneous reaction at the injection site, and B is the total number of 
injections.   
 
4.12.1.4 Flu-Like Reactions 
The following MedDRA preferred terms are determined by the Sponsor’s Pharmacovigilance 
personnel to be the flu-like reactions: 
• Influenza like illness 
• Pyrexia (or Feeling hot or Body temperature increased) plus at least two of the following 
symptoms: 
1. Chills 
2. Myalgia 
3. Arthralgia 
Only events that start on the day of injection or the day after injection will be included.   
The number and percentage of patients overall and by treatment group experiencing flu-like 
reactions will be tabulated.  
The percentage of injections leading to flu-like reactions will also be summarized.  The 
percentage of injections leading to flu-like reactions will be calculated for each patient as 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 67 of 68 
(A/B)*100, where A is the number of injections associated with a flu-like reaction, and B is the 
total number of injections.   
 
4.12.1.5 Renal Safety 
TEAEs in the MedDRA Acute renal failure SMQ (broad version), Nephropathies High Level 
Group Term (HLGT), Renal disorders NEC High Level Term (HLT), and Renal failure and 
impairment HLT, and any of following PTs are related to renal safety.  
• 
Nephritis 
• Glomerulonephritis proliferative 
• Glomerulonephritis acute 
• Glomerulonephritis rapidly progressive 
• C3 Glomerulonephritis 
• Chronic autoimmune glomerulonephritis 
• Glomerulonephritis chronic 
• Fibrillary glomerulonephritis 
• Glomerulonephritis membranoproliferative 
• Glomerulonephritis membranous 
• Glomerulonephritis minimal lesion 
• Henoch-Schonlein purpura nephritis 
• Immune mediated nephritis 
• Immunotactoid glomerulonephritis 
• Lupus nephritis 
• Nephritis allergic 
• Nephrotic syndrome 
 
A by-subject listing will be presented for those events. 
Number and percentage of subjects with events above will be provided.  
Kaplan-Meier plots for time from Day 1 of ION-682884 to first events above will be presented if 
there are sufficient number of events to make this feasible.  
 
4.12.2 Clinical Laboratory Evaluation 
Laboratory tests to ensure patient safety include chemistry panel, complete blood count with 
differential, thyroid panel, coagulation panel, immunogenicity, inflammatory panel, and urinalysis.  
For continuous laboratory tests, absolute values, change and percent change from Baseline will be 
summarized by visit and treatment group. No statistical comparisons between treatments will be 
conducted for these summaries.  Except for platelet counts, only central lab data will be 
summarized in tables and figures.  For platelet count, results from central and local laboratories 
will be included. 
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PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 68 of 69 
All laboratory test results will be listed.  Separate listings will be provided for local and central 
labs. The central lab listing will be based on the Analysis Data Model (ADaM) dataset and will 
include all central lab records. The local lab listing will be based on the Study Data Tabulation 
Model (SDTM) dataset. A separate listing for platelets that includes assessment from both the local 
and central labs will be provided.  A separate listing will contain only values outside of normal 
ranges. 
 
Unless otherwise specified, if the lab value with symbols (e.g., <, >, >=, <=, and ?), the symbol 
will be removed and the numerical value will be used for tables and figures.  The original values 
with symbol will be used in the listings.   
Except for ALT, AST, ALP, Bilirubin, Platelet and eGFR (see Section 4.12.2.1- 4.12.2.3), 
Selected laboratory parameters were classified by Common Terminology Criteria for Adverse 
Events (CTCAE v5.0) grade (Appendix 6.5). Shift tables from ION-682884 Baseline to worst 
post-treatment value will be provided. In addition, shift table for confirmed nadir hemoglobin 
will be presented.   
Additional investigation of hepatobiliary laboratory assessments, platelet counts, and renal 
parameters will be performed, and are detailed in the sections below. In this investigation, 
confirmed laboratory values will also be summarized.   
A confirmed laboratory value is based on consecutive lab values within 7 days. If that value is in 
the same or worse category the initial value is confirmed. If the consecutive value is in a better 
category then the initial value is confirmed in the better value category.  If there is no retest within 
7 days, then the initial value is presumed confirmed. If there are multiple results on the same day 
(no matter from the same lab vendor or different lab vendors), then the worst value will be utilized 
in the analysis. 
Selected central laboratory test results will be graphed by value (include scheduled and 
unscheduled visit) for individual patients (spaghetti plots over time).  Results from both central 
and local laboratory for platelets will be included in the spaghetti plot.  In addition, mean (±SE) by 
visit plot will be presented. 
 
4.12.2.1 Hepatobiliary Laboratory abnormalities 
The number and percentage of patients falling in each of the following categories based on post-
baseline assessments will be provided: 
• Alanine aminotransferase (ALT) ≥ 3 x Upper limit of normal (ULN)  
• ALT ≥ 5 x ULN 
• ALT ≥ 8 x ULN 
• ALT ≥ 10 x ULN 
• ALT ≥ 20 x ULN 
• Aspartate aminotransferase (AST) ≥ 3 x Upper limit of normal (ULN)  
• AST ≥ 5 x ULN 
• AST ≥ 8 x ULN 
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Statistical Analysis Plan 
 
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• AST ≥ 10 x ULN 
• AST ≥ 20 x ULN 
• Confirmed ALT ≥ 3 x ULN 
• Confirmed ALT ≥ 5 x ULN 
• Confirmed ALT ≥ 8 x ULN 
• Confirmed ALT ≥ 10 x ULN 
• Confirmed ALT ≥ 20 x ULN 
• Confirmed AST ≥ 3 x ULN 
• Confirmed AST ≥ 5 x ULN 
• Confirmed AST ≥ 8 x ULN 
• Confirmed AST ≥ 10 x ULN 
• Confirmed AST ≥ 20 x ULN 
• ALT ≥ 3 x ULN - < 5 x ULN 
• ALT ≥ 5 x ULN - < 10 x ULN 
• ALT ≥ 10 x ULN - < 20 x ULN 
• AST ≥ 3 x ULN - < 5 x ULN 
• AST ≥ 5 x ULN - < 10 x ULN 
• AST ≥ 10 x ULN - < 20 x ULN 
• Confirmed ALT ≥ 3 x ULN - < 5 x ULN 
• Confirmed ALT ≥ 5 x ULN - < 10 x ULN 
• Confirmed ALT ≥ 10 x ULN - < 20 x ULN 
• Confirmed AST ≥ 3 x ULN - < 5 x ULN 
• Confirmed AST ≥ 5 x ULN - < 10 x ULN 
• Confirmed AST ≥ 10 x ULN - < 20 x ULN 
• ALT ≥ 3 x ULN or ≥2 x ALT Baseline if ALT Baseline > ULN 
• AST ≥ 3 x ULN or ≥2 x AST Baseline if AST Baseline > ULN 
• Confirmed ALT ≥ 3x ULN or confirmed ALT ≥ 2 x ALT Baseline if ALT Baseline > ULN 
• Confirmed AST ≥ 3x ULN or confirmed AST ≥ 2 x AST Baseline if AST Baseline > ULN 
• Total bilirubin >= 2 x ULN 
• Confirmed total bilirubin >= 2 x ULN 
• International normalized ratio (INR) > 1.5 
• 
ALT > 3 x ULN at any time during Post-Baseline or AST > 3 x ULN at any time during Post-
Baseline  
o And with TBL > 2 x ULN at any time during Post-Baseline   
o And with TBL > 2 x ULN at any time during Post-Baseline and ALP < 2 x ULN at all 
the time during Post-Baseline, which is Potential Hy’s Law 
 
Shift tables from Baseline will be provided using the peak value and the confirmed peak value for 
ALT, AST, ALP and Bilirubin.  
• Categories for ALT and AST will be ≤ULN, >ULN - 3 x ULN, >3 x ULN – 5 x ULN, >5 
x ULN – 20 x ULN, and >20 x ULN   
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ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 70 of 71 
• Categories for ALP will be ≤ULN, >ULN - 2.5 x ULN, >2.5 x ULN – 5 x ULN, >5 x 
ULN – 20 x ULN, and >20 x ULN 
• Categories for Bilirubin will be ≤ULN, >ULN - 1.5 x ULN, >1.5 x ULN – 3 x ULN, >3 x 
ULN – 10 x ULN, and >10 x ULN 
 
For patients that had ALT elevation ≥ 3 x ULN, the time from first dose to first ALT elevation ≥ 3 
x ULN will be summarized using the following descriptive statistics: mean, SD, median, P25, P75, 
and minimum and maximum. Kaplan-Meier plots for time from Day 1 of ION-682884 to first ALT 
elevation ≥ 3 x ULN will be presented if there are sufficient number of events to make this feasible. 
Same analyses will be performed for AST. 
Shift tables from Baseline for ALT, AST, and total bilirubin based on peak (maximum) and 
confirmed peak category will also be provided based on CTCAE v5.0.  Note, in shift table ALT, 
AST, and BILI Baseline will be categorized as Normal and Abnormal based on LLN and ULN.  
 
4.12.2.2 Platelets 
The number and percentage of patients falling in each of the following categories (using available 
central and local laboratory assessments) based on post-Baseline assessments will be provided: 
• Platelet count - Grade 1a [≥ 100 x 109/L to <140 x 109/L]  
• Platelet count - Grade 1b [≥ 75 x 109/L to < 100 x 109/L]  
• Platelet count - Grade 2 [≥ 50 x 109/L to < 75 x 109/L] 
• Platelet count - Grade 3 [≥ 25 x 109/L to < 50 x 109/L] 
• Platelet count - Grade 4 [< 25 x 10^9/L] 
• Platelet count < 140 x 109/L 
• Platelet count < 100 x 109/L 
• Platelet count < 75 x 109/L 
• Platelet count < 50 x 109/L 
• Platelet count < 25 x 109/L 
• Maximum toxicity grade (Grade 1a, Grade 1b, Grade 2, Grade 3, Grade 4) 
• Confirmed maximum toxicity grade (Grade 1a, Grade 1b, Grade 2, Grade 3, Grade 4) 
• ≥ 30% decrease from Baseline 
• ≥ 50% decrease from Baseline 
• Confirmed ≥ 30% decrease from Baseline 
• Confirmed ≥ 50% decrease from Baseline 
• Confirmed platelet count - Grade 1a [≥ 100 x 109/L to < 140 x 109/L] 
• Confirmed platelet count - Grade 1b [≥ 75 x 109/L to < 100 x 109/L] 
• Confirmed platelet count - Grade 2 [≥ 50 x 109/L to < 75 x 19/L] 
• Confirmed platelet count - Grade 3 [≥ 25 x 109/L to < 50 x 109/L] 
• Confirmed platelet count - Grade 4 [< 25 x 109/L] 
• Confirmed value < 140 x 109/L 
• Confirmed value < 100 x 109/L 
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Statistical Analysis Plan 
 
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• Confirmed value < 75 x 109/L 
• Confirmed value < 50 x 109/L 
• Confirmed value < 25 x 109/L 
 
Furthermore, the platelet counts that define platelet count decrease grades are based on interactions 
with FDA, and align with the definitions from the National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5.0 (except that the CTCAE does not subdivide Grade 1 into 
Grade 1a and 1b).  
Shift tables from Baseline will be provided using the nadir value and the confirmed nadir category. 
Categories for the shift table will be ≥ 140 × 109/L, ≥ 100 × 109/L to < 140 × 109/L, ≥ 75 x 
109/L to < 100 x 109/L, ≥ 50 x 109/L to < 75 x 109/L, ≥ 25 x 109/L to < 50 x 109/L, and < 25 x 
109/L. 
For each of the platelet categories investigated, time from first dose to the onset will be summarized 
for the patients that met the criterion using the following descriptive statistics: mean, standard 
deviation, median, P25, P75, and minimum and maximum. Kaplan-Meier plots for time to first 
event will be provided for value < 100 x 109/L and value < 140 x1 09/L. 
Duration of platelet counts below 140 × 109/L or 100 x 109/L will be summarized, based on the 
duration (in weeks) each patient was below 140 × 109/L or 100 x 109/L.   
Note that a platelet value of 140 x 109/L is the lower limit of normal (LLN) for the central 
laboratory and will be used as the LLN for all platelet assessments, including those from local 
labs.   
The post-Baseline nadir (absolute value, change from Baseline, and percent change from Baseline) 
of platelet count will be summarized by treatment group and by Baseline platelet count categories: 
< 125× 109/L, ≥ 125 to < 150 × 109/L, ≥ 150 to < 175 × 109/L, ≥ 175 to < 200 × 109/L, and ≥ 200 × 
109/L. A listing of subjects in each group that had a nadir platelet count < 75 × 109/L (including 
the corresponding platelet nadir) will also be provided, if applicable.  
 
4.12.2.3 Renal parameters 
The number and percentage of patients falling in each of the following categories (using available 
central laboratory assessments) based on post-Baseline assessments will be provided: 
• Nadir creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) >= 90 mL/min/1.73m2 
• Nadir creatinine clearance by CKD-EPI >=60 mL/min/1.73m2 to < 90 mL/min/1.73m2 
• Nadir creatinine clearance by CKD-EPI >= 30 mL/min/1.73m2 to < 60 mL/min/1.73m2 
• Nadir creatinine clearance by CKD-EPI >= 15 mL/min/1.73m2 to < 30 mL/min/1.73m2 
• Nadir creatinine clearance by CKD-EPI < 15 mL/min/1.73m2 
• Creatinine clearance by CKD-EPI ≥ 25% decrease from Baseline 
• Creatinine clearance by CKD-EPI ≥ 50% decrease from Baseline 
• Urine Alb/C ratio > 5 x ULN 
• Urine P/C ratio > 5 x ULN 
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PAREXEL International 
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ION-682884-CS3 
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• Serum creatinine increase > 44.2 umol/l (0.5 mg/dL) from Baseline  
• Confirmed nadir creatinine clearance by CKD-EPI > =90 mL/min/1.73m2 
• Confirmed nadir creatinine clearance by CKD-EPI >=60 mL/min/1.73m2 to < 90 
mL/min/1.73m2 
• Confirmed nadir creatinine clearance by CKD-EPI >= 30 mL/min/1.73m2 to < 60 
mL/min/1.73m2 
• Confirmed nadir creatinine clearance by CKD-EPI >= 15 mL/min/1.73m2 to < 30 
mL/min/1.73m2 
• Confirmed nadir creatinine clearance by CKD-EPI < 15 mL/min/1.73m2 
• Confirmed creatinine clearance by CKD-EPI ≥ 25% decrease from Baseline 
• Confirmed creatinine clearance by CKD-EPI ≥ 50% decrease from Baseline 
• Confirmed urine Alb/C ratio > 5 x ULN 
• Confirmed urine P/C ratio > 5 x ULN 
• Confirmed serum creatinine increase > 44.2 umol (0.5 mg/dL) from Baseline  
• Urine protein/creatinine ratio (UPCR) > 3 × Baseline and > 1000 mg/g 
• UPCR > 5× Baseline AND > 1500 mg/g; or absolute UPCR value ≥ 2000 mg/g  
• UPCR > 5 × Baseline and > 1500 mg/g 
• UPCR ≥ 2000 mg/g 
The eGFR will be used under the equation below: 
- 
CKD-EPI formula (Levey et al. 2009) 
141 x min(Scr/κ, 1)^α × max(Scr/ κ, 1)^(-1.209) × 0.993^Age × 1.018[if female] × 1.159[if 
black]  where Scr is standardized serum creatinine in mg/dL,  κ is 0.7 for females and 0.9 for 
males,  α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, 
and max indicates the maximum of Scr/κ or 1. 
 
The more recent formulae that do not include a correction factor for race will not be used due to 
the demographic distribution of the patients in the study (only 4% black/African-American) 
 
Shift tables from ION-682884 Baseline for creatinine clearance by CKD-EPI will be provided 
using the nadir value and the confirmed nadir category.  Categories for the shift table will be ≥ 90 
mL/min/1.73m2, ≥ 60 mL/min/1.73m2 to < 90 mL/min/1.73m2, ≥ 30 mL/min/1.73m2 to < 60 
mL/min/1.73m2, ≥ 15 mL/min/1.73m2 to < 30 mL/min/1.73m2, and <15 mL/min/1.73m2.   
If applicable, a listing will be provided for patients who 1) continued treatment with eplontersen 
after having a UPCR ≥ 1000 mg/g, or 2) continued treatment with eplontersen after having a 
creatinine clearance by CKD-EPI <= 60 mL/min/1.73m2. 
 
4.12.3 Vital Signs, Weight, and Physical Findings 
Vital signs include systolic and diastolic blood pressure, pulse, respiratory rate, and temperature.  
Weight will also be analyzed.  Absolute values at each visit, change and percent change from 
Baseline to each visit in vital signs and weight will be summarized by treatment group.  No 
statistical comparisons between treatments will be performed for this summary. 
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ION-682884-CS3 
Statistical Analysis Plan 
 
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Shift table from Baseline to the highest value and lowest value at any visit will be presented, 
respectively. The tables will be repeated for the vital signs collected within 24 hours of treatment 
administration as well. 
• Systolic blood pressure: < 90 mmHg, ≥ 90 to ≤ 140 mmHg, > 140 to ≤ 160 mmHg, 
> 160 mmHg 
• Diastolic blood pressure: < 50 mmHg, ≥ 50 to ≤ 90 mmHg, > 90 to ≤ 100 mmHg, 
> 100 mmHg 
• Pulse rate: < 60 bpm, ≥ 60 to ≤ 100 bpm, > 100 bpm 
  
The number and percent of patients meeting any one of the following criteria will be summarized 
by visit and any visit.  
• Body weight: decrease of ≥ 7% from Baseline and increase of ≥ 7% from Baseline 
• Temperature: > 38.0 °C, < 36.0 °C 
• Respiratory rate: < 12 breaths/min, > 20 breaths/min 
• Systolic Blood Pressure: < 90 mmHg, >140 mmHg, > 160 mmHg 
• Diastolic Blood Pressure: < 50 mmHg, >90 mmHg, > 100 mmHg 
• Pulse Rate: < 60 bpm, > 100 bpm 
 
In addition, the number and percent of patients with treatment-associated abnormal heart rate and 
blood pressure will be presented. The definition of treatment-associated abnormal heart rate and 
blood pressure is the measurements within 24 hours of treatment administration and meets the 
criteria above.    
If the “time” of vital sign assessment on the next day is missing, then it will be treated as within 
24 hours of treatment administration. 
A Listing of treatment-associated abnormal heart rate and blood pressure will be presented. 
All test results will be graphed by value (include scheduled and unscheduled visit) for individual 
patients (spaghetti plots over time) and as aggregate graphs by treatment group (box plot over 
time). 
All vital signs and weight will be listed. Physical examination findings will also be listed. 
 
4.12.4 12-Lead Electrocardiograms (12-Lead ECG) 
Absolute values, change and percent change from Baseline in ventricular rate and ECG intervals 
(PR, RR, QRS, QT, QT interval corrected for heart rate [QTc], QTc interval calculated using 
Bazett's formula [QTcB] and QTc interval calculated using Fridericia’s formula [QTcF]) will be 
presented by treatment and visit.       
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QTcF = QT / (RR) 1/3, where RR= 60/VR 
QTcB = QT / (RR) 1/2, where RR= 60/VR 
Shift table from Baseline to the worst (highest) post-Baseline value by treatment group will be used 
to assess the change in the QTcF interval at any visit.  The categories for the shift table will be: 
≤450 msec, >450 msec to ≤480 msec, >480 msec to ≤500 msec, and >500 msec.   
The number and percent of patients with QTcF meeting any one of the following criteria at any 
post-baseline will be summarized by visit and any visit.  
• QTcF >450 msec 
• QTcF >480 msec 
• QTcF >500 msec 
• >30 msec higher than Baseline 
• >60 msec higher than Baseline 
This analysis will be presented overall and also by the subgroup based on  QTcF group (Normal, 
Abnormal)  at Baseline.  Normal QTcF will be defined as ≤450 msec for males or ≤470 msec for 
females.   
The number and percent of patients with overall qualitative ECG abnormalities will also be 
summarized. No statistical comparisons between treatments will be performed for these 
summaries. 
Ventricular rate and ECG intervals (PR, RR, QRS, QT, QTcB and QTcF), as well as treatment-
emergent abnormalities will be listed.   
All test results will be graphed by value (include scheduled and unscheduled visit) for individual 
patients (spaghetti plots over time) and as aggregate graphs by treatment group (box plot over 
time). 
The summaries above will be repeated by CM subgroup and Non-CM subgroup.  
The number and percent of patients with QRS>160 ms and >25% above Baseline will be 
summarized by visit and any visit.  
 
4.12.5 Pregnancy  
As applicable, the number and percent female patients with pregnancy during study and outcome 
of pregnancy will be summarized. As well as summary of all known AEs in patients’ offspring.  
 
4.12.6 Ocular Questionnaire 
The number and percentage of patients of ocular questionnaire will be summarized by visit and 
treatment group.  
 
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ION-682884-CS3 
Statistical Analysis Plan 
 
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4.12.7 Safety Monitoring (Data and Safety Monitoring Board [DSMB])  
DSMB will be assembled and meet periodically to review safety and tolerability data collected on 
ION‑682884 and inotersen, and to review the results of the predetermined interim analysis at Week 
35. Based on its assessment of the safety and of ION‑682884 and inotersen, 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 data are outlined in the DSMB Charter. 
 
4.13 
Determination of Sample Size 
The sample size for this study was estimated based on the data from the NEURO-TTR clinical 
trial. 
With 140 patients (120 of them dosed with ION-682884) and assuming a 10% dropout rate, there 
would be 108 evaluable patients treated with ION-682884. In the NEURO-TTR trial, there are 52 
evaluable placebo patients. 
It is observed that the NEURO-TTR placebo group had a 23.8 point increase in the mNIS+7 score 
from Baseline to Week 66. It is estimated that the ION-682884 group will have a 4.2 point increase 
in mNIS+7. The SD of the change from Baseline is estimated to be 20. There would be at least 
90% power to detect a 19.6 point difference in the change from Baseline of the mNIS+7 score 
between ION-682884-treated patients and the NEURO-TTR-placebo patients, with a 2-sided alpha 
level of 0.025. 
For the Norfolk QOL-DN, it is observed that the NEURO-TTR placebo group had 10.7 points 
change from Baseline to Week 66. It is estimated that the ION-682884-treated group will have a 0 
point change from Baseline. The SD is estimated to be 20. There would be at least 80% power to 
detect a 10.7 points difference in the change from Baseline of the Norfolk QOL-DN between ION-
682884-treated patients and the NEURO-TTR placebo patients, with a 2-sided alpha level of 0.025. 
For the TTR percent change from Baseline, it is observed that the NEURO-TTR placebo group 
had 9.7% reduction from Baseline to Week 65. It is estimated that the ION-682884-treated group 
will have at least 80% reduction from Baseline. The SD is estimated to be 13%. There would be at 
least 95% power to detect a 70.3% difference in the percent change from Baseline between ION-
682884-treated patients and the NEURO-TTR-placebo patients, with a 2-sided alpha level of 
0.025. 
 
4.14 
Changes in the Conduct of the Study or Planned Analysis 
No changes were made to the planned analyses in the Study Protocol. 
 
 
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5 
REFERENCES 
Carpenter J, Roger J, and Kenward M. (2013), “Analysis of Longitudinal Trials with Protocol 
Deviations: A Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation,” Journal of Biopharmaceutical Statistics, 23, 1352-1371. 
Huber, P. J. (1967), “The Behavior of Maximum Likelihood Estimates under Nonstandard 
Conditions,” Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and 
Probability, 1, 221–233. 
Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum 
creatinine and cystatin C. N Engl J Med 2012; 367: 20-29. 
Kenward, M. G. and Roger, J. H. (1997), "Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood," Biometrics, 53. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med 2009; 150: 604-612. 
Schafer JL. Analysis of Incomplete Multivariate Data. eBook 
http://www.ii.uni.wroc.pl/~bitro/wojtki/e_book/Analisis/4061fm.pdf. Chapman and Hall/CRC 
1997: 
Schafer JL. Multiple imputation: a primer. Stat Methods Med Res 1999; 8: 3-15. 
Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, Quarmby V, Richards 
S, Schneider CK, Subramanyam M, Swanson S, Verthelyi D, Yim S. “Assessment and Reporting 
of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology 
and Tactical Recommendations.” AAPS Journal: 16(4), 658 – 673. 
Wang YM, Wang J, Hon YY, Zhou L, Fang L, Ahn HY (2016), “Evaluating and Reporting the 
Immunogenicity Impacts for Biological Products--a Clinical Pharmacology Perspective.” AAPS 
J.:18(2):395-403. 
Westfall PH Young SS. Resampling-based Multiple Testing: Examples and Methods for p-Value 
Adjustment. In: Wiley Series in Probability and Statistics. John Wiley & Sons Inc. New York; 
1993: 1-360. 
 
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IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 77 of 78 
6 Appendix 
6.1 Components and Subcomponents of the mNIS+7 
 
 
Figure 3 Components and Subcomponents of the mNIS+7 
 
 
 
 
 
 
 
 
 
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ION-682884-CS3 
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Related to:  SOP-GDO-WW-019                                                                                                               Page 82 of 83 
6.2 
Scoring of Assessment Instruments 
Neuropathy Symptoms and Change (NSC) 
The NSC questionnaire consists of 38 questions asking about different symptoms. 
A symptom is marked as present if in the judgment of the examining neurologist, it occurs more 
frequently or more severely than in healthy persons of the same age and gender and is due to 
neuropathy.  If a symptom is present its severity is graded as 1 (slight +), 2 (moderate ++) or 3 
(severe +++).  If the symptom is not present it is given a score of 0. 
Two questions (35 and 36) are only answered by men.  These are not included in the score for 
women. 
The questions in the NSC can be divided into the following domains 
• Muscle weakness:  
 
 
 
       Questions 1-19 
• Sensory (hypo / loss of sensation):     
       Questions 20-22 
• Sensory (paresthesia, hyper sensation):   
       Questions 23 - 29  
• Autonomic (GI/urinary incontinence):   
       Questions 31, 32, 33, 34 
• Autonomic (other than GI/urinary incontinence): Questions 30, 35-38 for men 
                                                            
        Questions 30, 37-38 for women 
The Muscle weakness domain is also divided into 4 sub-domains: 
• Head and Neck: 
 
            Questions 1-6 
• Chest: 
 
 
 
Questions 7-9 
• Upper Limbs: 
 
 
Questions 10-15 
• Lower Limbs: 
 
 
Questions 16-19 
For each sub-domain and domain the total score is obtained by summing the relevant questions.  
The maximum score is therefore 57 for muscle weakness, 9 for Sensory (hypo / loss of sensation), 
21 for Sensory (paresthesia, hyper sensation), 12 for Autonomic (GI/urinary incontinence), 15 for 
Autonomic (other than GI/urinary incontinence) in men and 9 for Autonomic (other than 
GI/urinary incontinence) in women.  The minimum score is zero for each domain. 
The NSC total score is the sum of the scores across all 5 domains.  The minimum NSC total score 
is therefore 0 and the maximum NSC total score is 114 for men and 108 for women. 
For questions 20-29 the location affected is also collected on the questionnaire but this information 
is not used in the calculation of the domain or total scores. 
 
 
 
 
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6.3 
Composite Autonomic Symptom Score (COMPASS-31) 
 
Table 3: COMPASS-31 Scores 
 
Domain 
Item 
Answer 
Points 
Orthostatic Intolerance 
1 
1.Yes 
1 
 
 
2.No 
0 
 
2 
1.Rarely 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Almost always 
3 
 
3 
1.Mild 
1 
 
 
2.Moderate 
2 
 
 
3.Severe 
3 
 
4 
1.Gotten much worse 
3 
 
 
2.Gotten somewhat worse 
2 
 
 
3.Stayed about the same 
1 
 
 
4.Gotten somewhat better 
0 
 
 
5.Gotten much better 
0 
 
 
6.Completely gone 
0 
Vasomotor 
5 
1.Yes 
1 
 
 
2.No 
0 
 
6 
1.Hands 
1 
 
 
2.Feet 
1 
 
7 
1.Getting much worse 
3 
 
 
2.Getting somewhat worse 
2 
 
 
3.Stayed about the same 
1 
 
 
4.Getting somewhat better 
0 
 
 
5.Getting much better 
0 
 
 
6.Completely gone 
0 
Secretomotor 
8 
1.I sweat much more than I used to 
1 
 
 
2.I sweat somewhat more than I used to 
0 
 
 
3.I haven’t noticed any change 
0 
 
 
4.I sweat somewhat less than I used to 
1 
 
 
5.I sweat much less than I used to 
2 
 
9 
1.Yes 
1 
 
 
2.No 
0 
 
10 
1.Yes 
1 
 
 
2.No 
0 
 
11 
1.I have not had any of these symptoms 
0 
 
 
2.Getting much worse 
3 
 
 
3.Getting somewhat worse 
2 
 
 
4.Staying about the same 
1 
 
 
5.Getting somewhat better 
0 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 84 of 85 
Domain 
Item 
Answer 
Points 
 
 
6.Getting much better 
0 
 
 
7.Completely gone 
0 
Gastrointestinal 
12 
1.I get full a lot more quickly now than I used to 
2 
 
 
2.I get full more quickly now than I used to 
1 
 
 
3.I haven’t noticed any change 
0 
 
 
4.I get full less quickly now than I used to 
0 
 
 
5.I get full a lot less quickly now than I used to 
0 
 
13 
1.Never 
0 
 
 
2.Sometimes 
1 
 
 
3.A lot of the time 
2 
 
14 
1.Never 
0 
 
 
2.Sometimes 
1 
 
 
3.A lot of the time 
2 
 
15 
1.Never 
0 
 
 
2.Sometimes 
1 
 
 
3.A lot of the time 
2 
 
16 
1.Yes 
1 
 
 
2.No 
0 
 
17 
1.Rarely 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Constantly 
3 
 
18 
1.Mild 
1 
 
 
2.Moderate 
2 
 
 
3.Severe 
3 
 
19 
1.Much worse 
3 
 
 
2.Somewhat worse 
2 
 
 
3.Staying the same 
1 
 
 
4.Somewhat better 
0 
 
 
5.Much better 
0 
 
 
6.Completely gone 
0 
 
20 
1.Yes 
1 
 
 
2.No 
0 
 
21 
1.Rarely 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Constantly 
3 
 
22 
1.Mild 
1 
 
 
2.Moderate 
2 
 
 
3.Severe 
3 
 
23 
1.Much worse 
3 
 
 
2.Somewhat worse 
2 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 85 of 86 
Domain 
Item 
Answer 
Points 
 
 
3.Staying the same 
1 
 
 
4.Somewhat better 
0 
 
 
5.Much better 
0 
 
 
6.Completely gone 
0 
Bladder 
24 
1.Never 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Constantly 
3 
 
25 
1.Never 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Constantly 
3 
 
26 
1.Never 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Constantly 
3 
Pupillomotor 
27 
1.Never 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Constantly 
3 
 
28 
1.Mild 
1 
 
 
2.Moderate 
2 
 
 
3.Severe 
3 
 
29 
1.Never 
0 
 
 
2.Occasionally 
1 
 
 
3.Frequently 
2 
 
 
4.Constantly 
3 
 
30 
1.Mild 
1 
 
 
2.Moderate 
2 
 
 
3.Severe 
3 
 
31 
1. I have not had any of these symptoms 
0 
 
 
2.Much worse 
3 
 
 
3.Somewhat worse 
2 
 
 
4.Staying the same 
1 
 
 
5.Somewhat better 
0 
 
 
6.Much better 
0 
 
 
7.Completely gone 
0 
 
 
 
 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 86 of 87 
6.4 
Sample Programming code for Final Alpha 
Below is the sample SAS code for the calculation of the alpha used in the final analysis.   
 
Step 1: obtain the correlation coefficient between interim analysis and final analysis. 
Let T1 and T2 be the standardized test statistics at the interim and final analyses, respectively. In 
order to determine the alpha level for the final analysis, the correlation between T1 and T2 is 
first estimated based on the resampling approach: 
 
• Among the 108 ION-682884-treated patients and 52 NEURO-TTR placebo patients, 
randomly assign 108 patients to the ION-682884 treated group and 52 patients to 
NEURO-TTR placebo group 
• Apply the re-randomized treatment assignment to the interim data and obtain the 
standardized test statistics T1 
• Apply the re-randomized treatment assignment to the final data and obtain the 
standardized test statistics T2 
• Repeat the above procedure N times (N = 10000) and obtain N pairs of test statistics T1 
and T2. 
• A random seed of 2855 will be used to generate N times resampling. 
 
%macro simulation(seed=xx); 
%do i=1 %to 10000; 
data adsl; 
  set adsl; 
  x=ranuni(%eval(&seed+&i)); 
run; 
 
proc sort;  by x; run; 
 
data adsl; 
  set adsl; 
  by x; 
  if _n_<=52 then treatment=1; 
  else treatment=2; 
run; 
 
data Interim&i; 
  merge InterimData adsl; 
  by subject_id; 
  trial=&i; 
run; 
 
data Final&i; 
  merge FinalData adsl; 
  by subject_id; 
  trial=&i; 
run; 
 
%end; 
 
data Interim; 
  set %do i=1 %to 10000; Interim&i %end;; 
run; 
 
data Final; 
  set %do i=1 %to 10000; Final&i %end;; 
run; 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 87 of 88 
%mend; 
 
%simulation(seed=nn); 
ods output diffs=diff35(rename=(tvalue=t35); 
PROC MIXED DATA=interim; 
  By trial; 
  CLASS treatment visit subject_id PRETRTI DISTAI V30TTRI; 
  MODEL endpoint=treatment baseline PRETRTI DISTAI V30TTRI visit visit*baseline visit*treatment / DDFM=kr; 
  REPEATED visit / SUBJECT=subject_id TYPE=un; 
  LSMEANS visit*treatment / CL DIFF=control("1" "35"); 
  Weight wt; 
RUN; 
 
ods output diffs=diff66(rename=(tvalue=t66); 
PROC MIXED DATA=Final;  
  By trial; 
  CLASS treatment visit subject_id PRETRTI DISTAI V30TTRI; 
  MODEL endpoint=treatment baseline PRETRTI DISTAI V30TTRI visit visit*baseline visit*treatment / DDFM=kr; 
  REPEATED visit / SUBJECT=subject_id TYPE=un; 
  LSMEANS visit*treatment / CL DIFF=control("1" "66"); 
  Weight wt; 
RUN; 
data diff; 
  merge diff35 diff66; 
   by trial; 
run; 
 
The correlation between T1 and T2 will then be estimated as the sample correlation of the N pairs. 
 
proc corr; 
  var t35 t66; 
run; 
 
Step 2: Below is the sample SAS code for the calculation of the alpha used in the final analysis.  In 
this example, the correlation coefficient (r) between T1 and T2 is assumed to be 0.636, and two-
side alpha 0.025 is used for interim analysis. Overall alpha is 0.05.  The following SAS code will 
create the final two-sided alpha to be used.   
 
proc fcmp; 
   function totalalpha(corr, ts1, ts2); 
      p1=cdf('NORMAL',ts1); /*probability for T1 up to ts1 (interim analysis), T2 up 
to infinity.  This is marginal prob in the interim analysis. */ 
      p2=cdf('NORMAL',ts2); /*probability for T1 up to infinity, T2 up to ts2.*/ 
      p3=probbnrm(ts1,ts2,corr); /*joint probability for T1 up to ts1 (interim 
analysis), T2 up to ts2 . */ 
      return(2*(p1+p2-p3)-0.05); 
   endsub; 
 
   array opts[5] initial abconv relconv maxiter status (0 1.0e-12 1.0e-6 1000 -1); 
 
   corr=0.636; 
   ts1=quantile('NORMAL',0.025/2); 
   ts2=solve("totalalpha", opts, 0, corr, ts1, .); /*this is the two-side alpha for 
the final analysis.*/ 
 
   /* result */ 
   ts1p=cdf('NORMAL',ts1); 
   ts2p=cdf('NORMAL',ts2); 
   p1=cdf('NORMAL',ts1); 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 88 of 89 
   p2=cdf('NORMAL',ts2); 
   p3=probbnrm(ts1,ts2,corr); 
   totalalpha=(p1+p2-p3)*2; 
   final=p2*2; 
   put "cor =" corr; 
   put "ts1 =" ts1 "; ts1 prob =" ts1p; 
   put "ts2 =" ts2 "; ts2 prob =" ts2p; 
   put "total alpha =" totalalpha; 
   put "alpha level for final analysis =" final; 
 
run; 
 
 
 
 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 89 of 90 
6.5 
Laboratory Parameters’ Classification by CTCAE v5.0 
Selected Laboratory Parameters’ Classification by CTCAE v5.0. Of note, grade 0 was added to 
present normal lab value.  
Chemistry Lab Tests 
Creatine kinase  
Grade 0: ≤ ULN, Grade 1: > ULN – 2.5 x ULN, Grade 2: > 2.5 – 5.0 x ULN, Grade 3: > 5.0 – 10.0 
x ULN, Grade 4: > 10.0 x ULN. 
The worst value should be the peak value. 
 Serum creatinine 
Grade 0: ≤ ULN, Grade 1: > ULN – 1.5 x ULN, Grade 2: > 1.5 – 3.0 x ULN or > 1.5 - 3.0 x 
baseline, Grade 3:  > 3.0 – 6.0 x ULN or > 3.0 x baseline, Grade 4: > 6.0 x ULN. 
The worst value should be the peak value. 
 Calcium (increased) (mmol/L) 
Grade 0: corrected serum calcium of ≤ ULN, Grade 1: corrected serum calcium of > ULN – 2.9 
mmol/L, Grade 2: corrected serum calcium of > 2.9 – 3.1 x mmol/L, Grade 3: corrected serum 
calcium of > 3.1 – 3.4 mmol/L, Grade 4: > 3.4 mmol/L. 
 The worst value should be the peak value. 
 Calcium (decreased) (mmol/L) 
Grade 0: corrected serum calcium of ≥ LLN, Grade 1: corrected serum calcium of < LLN – 2.0 
mmol/L, Grade 2: corrected serum calcium of < 2.0 – 1.75 mmol/L, Grade 3: corrected serum 
calcium of < 1.75 – 1.5 mmol/L, Grade 4: corrected serum calcium of < 1.5 mmol/L. 
The worst value should be the nadir value. 
Glucose (decreased) (mmol/L) 
Grade 0: fasting glucose value ≥ LLN, Grade 1: fasting glucose value < LLN – 3.0 mmol/L, Grade 
2: fasting glucose value < 3.0 – 2.2 mmol/L, Grade 3: fasting glucose value < 2.2 – 1.7 mmol/L, 
Grade 4: fasting glucose value <1.7 mmol/L. 
The worst value should be the nadir value. 
  
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 90 of 91 
Potassium (increased) (mmol/L) 
Grade 0: ≤ ULN, Grade 1: > ULN – 5.5 mmol/L, Grade 2: > 5.5 – 6.0 mmol/L, Grade 3: > 6.0 – 
7.0 mmol/L, Grade 4: > 7.0 mmol/L. 
The worst value should be the peak value. 
 Potassium (decreased) (mmol/L) 
Grade 0: ≥ LLN, Grade 1: < LLN – 3.0 mmol/L, Grade 2: Symptomatic with < LLN – 3.0 mmol/L 
intervention indicated, Grade 3:  < 3.0 – 2.5 mmol/L, Grade 4: <2.5 mmol/L. 
The worst value should be the nadir value. Note, since grade 1 and grade 2 has same numerical 
criteria, go with grade 2. 
 Magnesium (increased) (mmol/L) 
Grade 0: ≤ ULN, Grade 1: > ULN – 1.23 mmol/L, Grade 2: -, Grade 3: > 1.23 – 3.30 mmol/L, 
Grade 4: > 3.30 mmol/L. 
The worst value should be the peak value. 
 Magnesium (decreased) (mmol/L) 
Grade 0: ≥ LLN, Grade 1: < LLN – 0.5 mmol/L, Grade 2: < 0.5 – 0.4 mmol/L, Grade 3: < 0.4 – 
0.3 mmol/L, Grade 4: <0.3 mmol/L. 
The worst value should be the nadir value. 
 Sodium (increased) (mmol/L) 
Grade 0: ≤ ULN, Grade 1: > ULN – 150 mmol/L, Grade 2: > 150 – 155 mmol/L, Grade 3: > 155 
– 160 mmol/L, Grade 4: > 160 mmol/L. 
The worst value should be the peak value. 
 Sodium (decreased) (mmol/L) 
Grade 0: ≥ LLN, Grade 1: < LLN – 130 mmol/L, Grade 2: 125-129 mmol/L and asymptomatic, 
Grade 3: 125-129 mmol/L symptomatic; 120-124 mmol/L regardless of symptoms, Grade 4: < 120 
mmol/L. 
The worst value should be the nadir value. Note, grade 3 and grade 2 has same numerical criteria. 
Go with Grade 3 
 Albumin (decreased) (g/L) 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 91 of 92 
Grade 0: ≥ LLN, Grade 1: < LLN – 30 g/L, Grade 2: < 30 – 20 g/L, Grade 3: <20 g/L. 
The worst value should be the nadir value. 
  
Haematology Lab Tests 
Hemoglobin (increased) (g/L) 
Grade 0:Increase <=0, Grade 1: Increase in >0 - 20 g/L, Grade 2: Increase in >20 - 40 g/L, Grade 
3:  Increase in >40 g/L. 
The worst value should be the peak value. 
Hemoglobin (decreased) (g/L) 
Grade 0: Hemoglobin (Hgb)≥ LLN, Grade 1:  < LLN – 100 g/L, Grade 2:  < 100 – 80 g/L, Grade 
3:  < 80 g/L. 
The worst value should be the nadir value. 
Lymphocyte count (increased) (10^9/L) 
Grade 0: <=4 x 10^9, Grade 2: > 4 x 10^9/L – 20 x 10^9/L, Grade 3: > 20 x 10^9/L. 
The worst value should be the peak value. 
Lymphocyte count (decreased) (10^9/L) 
Grade 0: ≥ LLN, Grade 1: < LLN – 0.8 x 10^9/L, Grade 2: < 0.8 – 0.5 x 10^9/L, Grade 3: < 0.5 - 
0.2 x 10^9/L, Grade 4: < 0.2 x 10^9/L. 
The worst value should be the nadir value. 
Neutrophil count decreased (10^9/L) 
Grade 0: ≥ 1.8 x 10^9/L, Grade 1: < 1.8 – 1.5 x 10^9/L, Grade 2: < 1.5 – 1.0 x 10^9/L, Grade 3: < 
1.0 - 0.5 x 10^9/L, Grade 4: < 0.5 x 10^9/L. 
The worst value should be the nadir value. Note, grade 1 was modified from CTCAT v5.0 
WBC (increased) (10^9/L) 
Grade 0: Grade 0 is <=100 x 10^9/L , Grade 3: > 100 x 10^9/L. 
The worst value should be the peak value. 
WBC (decreased) (10^9/L) 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 92 of 93 
Grade 0: ≥ LLN, Grade 1: < LLN – 3.0 x 10^9/L, Grade 2: < 3.0 – 2.0 x 10^9/L, Grade 3: < 2.0 
– 1.0 x 10^9/L, Grade 4: < 1.0 x 10^9/L. 
The worst value should be the nadir value 
 
Coagulation Lab Tests 
aPTT (Unit) 
Grade 0: ≤ ULN,  Grade 1: > ULN – 1.5 x ULN, Grade 2: > 1.5 – 2.5 x ULN, Grade 3:  > 2.5 x 
ULN ; bleeding. 
The worst value should be the peak value. 
 
INR (Unit) 
Grade 0: <=1.2, Grade 1: >1.2 – 1.5, Grade 2: > 1.5 – 2.5, Grade 3:  > 2.5 ; 
The worst value should be the peak value.  
 
 
 
 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
ION-682884-CS3 
Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
 Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019 
 Page 93 of 94 
6.6 
List of Changes in the Statistical Analysis Plan 
List of Changes in Version 2.1 
SAP Section(s) 
Impacted 
Description of Modification 
Overall 
Updated document version to 2.1 to correct section numbering throughout 
SAP 
1 
Updated to current versions of protocols used. 
2.4.1 
Updated efficacy objectives: 
To evaluate the efficacy of ION-682884 in the Change from Baseline in the 
Patient Global Impression of Severity (PGIS) and Patient Global Impression 
of Change (PGIC) at Weeks 37 and 85. To evaluate the efficacy of ION-
682884, as compared to the historical control of the placebo arm included in 
the ALN-TTR02-004 (APOLLO trial, ClinicalTrials.gov Identifier: 
NCT01960348) in the following measures at Week 85. 
4.1.7 
Updated SF-36 version to Quality Metric PRO CoRE Smart Measurement 
System, PRO CoRE Version 2.1. 
4.1.8 
Updated MedDRA version to 25.0 or later and WHODRUG to Mar2022 or 
later. 
Update as 4.2.1.1 
Added: 
Baseline ECG will be defined as the value taken on Day 1 pre-dose. If the 
triplicates are taken, the average of the triplicates will be used.   
4.2.1.2 
ION-682884 baseline will be defined as the last non-missing assessment prior 
to the first dose of ION-682884.  
4.2.3 
Updated Analysis Visit Windows for Serum TTR. 
4.5.4 
Added: 
PPS will be defined separately for interim analysis at Week 35 and final 
analysis at Week 66. 
4.6 
Added serum TTR and High-Sensitivity Troponin T in the summary 
part. 
4.6 
Added the genotyping category: 
The TTR genotype category will be summarized by V30M vs. Non-V30M.  
The V30M genotype category includes V30M Mutation (‘Yes’) and 
VAL50MET, V50M MUTATION, V50M and P.VAL50MET listed under 
the “Other” category in CRF.    
4.9 
Added: 
Duration of drug exposure (month) and total amount of ION-682884 
administered (mg) will be summarized by baseline platelet count categories < 
125 × 109/L, ≥ 125 to < 150 × 109/L, ≥ 150 to < 175 × 109/L, ≥ 175 to < 200 
× 109/L, and ≥ 200 × 109/L. 
4.10.1 
Reference to ELISA assay corrected to ECL assay 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 94 of 95 
SAP Section(s) 
Impacted 
Description of Modification 
4.10.2.1 
For primary analysis using MMRM, added additional options in case there 
are convergence issues. 
4.10.3.1 
Specify Sensitivity Analysis 2 to 4 apply to which endpoint at interim and 
final analysis: 
These sensitivity analyses will be applied for serum TTR in the Week 
35 interim analysis and serum TTR, mNIS+7, and Norfolk in Week 66 
final analyses. 
4.10.3.1 
Added the Sensitivity Analysis 6 for Norfolk. 
4.10.3.1 
Added Sensitivity Analysis 8 (Observed data) for mNIS+7 and Norfolk at 
week 35 interim analysis. 
4.10.4 
Added the ANCOVA model for mNIS+7 and Norfolk at week 35 interim 
analysis. 
Added subgroups of FAC Clinical Diagnosis from CRF and CM subgroup. 
 
4.10.7 
Added analysis for log-transformed NT-proBNP and Troponin T 
 
 
4.11.3.3 
Added: 
Lastly, other stratifications (e.g., based on antibody titer, onset of ADA, 
subjects with treatment-emergent ADA vs. treatment-unaffected ADA etc.) 
4.12.1 
Added imputation rule for partial missing date in adverse event 
4.12.1 
Added CM subgroup for analysis. 
 
 
4.12.1 
Added AE summary table for incidence rate and event rate per 100 
patient years of exposure.  
4.12.1.1 
Updated the definition of AESI and other AE of special interest. 
 
4.12.1.3 
Added a section for local cutaneous reactions at injection site (LCRIS) and 
Injection site reaction: 
- 
Injection Site Reaction (ISR) defined as TEAEs with MedDRA preferred 
terms contains text “Injection site”. ISR will be summarized by SOC and 
PT. In addition, ISR will be summarized by SOC, PT and injection 
location which is the location of the last injection prior to AE onset. 
- 
The following MedDRA preferred terms are determined by the Sponsor’s 
Pharmacovigilance personnel to represent the Local Cutaneous Reactions 
at Injection Site (LCRIS):  
• 
Injection site erythema 
• 
Injection site swelling  
• 
Injection site pruritus 
• 
Injection site pain 
• 
Injection site tenderness 
Events that start on the day of injection and persist for at least two days, i.e. 
event onset date on the day of injection and resolution date not on the day of 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 95 of 96 
SAP Section(s) 
Impacted 
Description of Modification 
injection or the day after the injection, will be included.  Events with onset 
date on the day of injection and missing resolution date will also be included.  
 
 
4.12.1.4 
Added a section for flu-like reactions: 
The following MedDRA preferred terms are determined by the Sponsor’s 
Pharmacovigilance personnel to be the flu-like reactions: 
• Influenza like illness 
• Pyrexia (or Feeling hot or Body temperature increased) plus at least two 
of the following symptoms: 
1. Chills 
2. Myalgia 
3. Arthralgia 
 
  
4.12.1.5 
Added TEAE related renal safety.  
4.12.2 
Appendix 6.5 
Added CTCAE v5.0 
 
4.12.2.1 
Added: 
ALT, AST, ALP and Bilirubin category criteria for shift table.  
• Categories for ALT and AST will be ≤ULN, >ULN - 3 x ULN, >3 x ULN 
– 5 x ULN, >5 x ULN – 20 x ULN, and >20 x ULN   
• Categories for ALP will be ≤ULN, >ULN - 2.5 x ULN, >2.5 x ULN – 5 x 
ULN, >5 x ULN – 20 x ULN, and >20 x ULN 
• Categories for Bilirubin will be ≤ULN, >ULN – 1.5 x ULN, >1.5 x ULN 
– 3 x ULN, >3 x ULN – 10 x ULN, and >10 x ULN 
4.12.2.2 
Added platelet summary table by baseline platelet category. 
 
 
4.12.2.3 
Added: 
Shift tables from ION-682884 baseline for creatinine clearance by CKD-EPI 
will be provided using the nadir value and the confirmed nadir category.   
4.12.3 
Added vital signs shift tables, and add vital signs summary table based on 
data collected within 24 hours of treatment administration. 
4.12.4 
Added: 
The number and percent of patients with QTcF meeting any one of the 
following criteria at any post-baseline will be summarized by visit and any 
visit.  
• QTcF >450 msec 
• QTcF >480 msec 
• QTcF >500 msec 
• >30 msec higher than Baseline 
• >60 msec higher than Baseline 
4.12.5  
Added Section 4.12.5 Pregnancy 
682884-CS03   Statistical Analysis Plan    03 Jun 2022 | 1.0


PAREXEL International 
IONIS PHARMACEUTICALS, INC. 
 
ION-682884-CS3 
Statistical Analysis Plan 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
      Project Document Version No. 2.1 
Effective Date:  30 Jan 19 
   Project Document Effective Date: 03Jun2022 
Related to:  SOP-GDO-WW-019                                                                                                               Page 96 of 96 
SAP Section(s) 
Impacted 
Description of Modification 
4.12.6 
Removed shift tables from Baseline in ocular questionnaire will be also 
summarized by visit and treatment group. 
 
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